Heterocyclylamines as PI3K inhibitors

ABSTRACT

The present invention provides heterocyclylamine derivatives of Formula I: 
                         
wherein the variables are defined herein, that modulate the activity of phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

This application is a continuation of U.S. Ser. No. 14/872,881, filedOct. 1, 2015, which is a continuation of U.S. Ser. No. 13/601,349, filedAug. 31, 2012, which claims the benefit of U.S. Prov. Appl. No.61/530,866, filed Sep. 2, 2011, U.S. Prov. Appl. No. 61/594,882, filedFeb. 3, 2012, and U.S. Prov. Appl. No. 61/677,445, filed Jul. 30, 2012,each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention provides heterocyclylamine derivatives, forexample, pyrazolopyrimidines, that modulate the activity ofphosphoinositide 3-kinases (PI3Ks) and are useful in the treatment ofdiseases related to the activity of PI3Ks including, for example,inflammatory disorders, immune-based disorders, cancer, and otherdiseases.

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipidsignaling kinases that phosphorylate phosphoinositides at the D3position of the inositol ring (Cantley, Science, 2002,296(5573):1655-7). PI3Ks are divided into three classes (class I, II,and III) according to their structure, regulation and substratespecificity. Class I PI3Ks, which include PI3Kα, PI3Kβ, PI3Kγ, andPI3Kδ, are a family of dual specificity lipid and protein kinases thatcatalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate(PIP₂) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP₃).PIP₃ functions as a second messenger that controls a number of cellularprocesses, including growth, survival, adhesion and migration. All fourclass I PI3K isoforms exist as heterodimers composed of a catalyticsubunit (p110) and a tightly associated regulatory subunit that controlstheir expression, activation, and subcellular localization. PI3Kα,PI3Kβ, and PI3Kδ associate with a regulatory subunit known as p85 andare activated by growth factors and cytokines through a tyrosinekinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002,277(44):41556-62) whereas PI3Kγ associates with two regulatory subunits(p101 and p84) and its activation is driven by the activation ofG-protein-coupled receptors (Brock, et al., J Cell Biol., 2003,160(1):89-99). PI3Kα and PI3Kβ are ubiquitously expressed. In contrast,PI3Kγ and PI3Kδ are predominantly expressed in leukocytes(Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).

The differential tissue distribution of the PI3K isoforms factors intheir distinct biological functions. Genetic ablation of either PI3Kα orPI3Kβ results in embryonic lethality, indicating that PI3Kα and PI3Kβhave essential and non-redundant functions, at least during development(Vanhaesebroeck, et al., 2005). In contrast, mice which lack PI3Kγ andPI3Kδ are viable, fertile and have a normal life span although they showan altered immune system. PI3Kγ deficiency leads to impaired recruitmentof macrophages and neutrophils to sites of inflammation as well asimpaired T cell activation (Sasaki, et al., Science, 2000,287(5455):1040-6). PI3Kδ-mutant mice have specific defects in B cellsignaling that lead to impaired B cell development and reduced antibodyresponses after antigen stimulation (Clayton, et al., J Exp Med. 2002,196(6):753-63; Jou, et al., Mol Cell Biol. 2002, 22(24):8580-91;Okkenhaug, et al., Science, 2002, 297(5583): 1031-4).

The phenotypes of the PI3Kγ and PI3Kδ-mutant mice suggest that theseenzymes may play a role in inflammation and other immune-based diseasesand this is borne out in preclinical models. PI3Kγ-mutant mice arelargely protected from disease in mouse models of rheumatoid arthritis(RA) and asthma (Camps, et al., Nat Med. 2005, 11(9):936-43; Thomas, etal., Eur J Immunol. 2005, 35(4):1283-91). In addition, treatment ofwild-type mice with a selective inhibitor of PI3Kγ was shown to reduceglomerulonephritis and prolong survival in the MRL-lpr model of systemiclupus nephritis (SLE) and to suppress joint inflammation and damage inmodels of RA (Barber, et al., Nat Med. 2005, 11(9):933-5; Camps, et al.,2005). Similarly, both PI3Kδ-mutant mice and wild-type mice treated witha selective inhibitor of PI3Kδ have been shown to have attenuatedallergic airway inflammation and hyper-responsiveness in a mouse modelof asthma (Ali, et al., Nature. 2004, 431(7011):1007-11; Lee, et al.,FASEB J. 2006, 20(3):455-65) and to have attenuated disease in a modelof RA (Randis, et al., Eur. J. Immunol., 2008, 38(5):1215-24).

In addition to their potential role in inflammatory diseases, all fourclass I PI3K isoforms may play a role in cancer. The gene encoding p110αis mutated frequently in common cancers, including breast, prostate,colon and endometrial (Samuels, et al., Science, 2004, 304(5670):554;Samuels, et al., Curr Opin Oncol. 2006, 18(1):77-82). Eighty percent ofthese mutations are represented by one of three amino acid substitutionsin the helical or kinase domains of the enzyme and lead to a significantupregulation of kinase activity resulting in oncogenic transformation incell culture and in animal models (Kang, et al., Proc Natl Acad Sci USA.2005, 102(3):802-7; Bader, et al., Proc Natl Acad Sci USA. 2006,103(5):1475-9). No such mutations have been identified in the other PI3Kisoforms although there is evidence that they can contribute to thedevelopment and progression of malignancies. Consistent overexpressionof PI3Kδ is observed in acute myeloblastic leukemia (Sujobert, et al.,Blood, 2005, 106(3):1063-6) and inhibitors of PI3Kδ can prevent thegrowth of leukemic cells (Billottet, et al., Oncogene. 2006,25(50):6648-59). Elevated expression of PI3Kγ is seen in chronic myeloidleukemia (Hickey, et al., J Biol Chem. 2006, 281(5):2441-50).Alterations in expression of PI3Kβ, PI3Kγ and PI3Kδ have also beenobserved in cancers of the brain, colon and bladder (Benistant, et al.,Oncogene, 2000, 19(44):5083-90; Mizoguchi, et al., Brain Pathol. 2004,14(4):372-7; Knobbe, et al., Neuropathol Appl Neurobiol. 2005,31(5):486-90). Further, these isoforms have all been shown to beoncogenic in cell culture (Kang, et al., 2006).

Thus, new or improved agents which inhibit kinases such as PI3K arecontinually needed for developing new and more effective pharmaceuticalsthat are aimed at augmentation or suppression of the immune andinflammatory pathways (such as immunosuppressive agents for organtransplants), as well as agents for the prevention and treatment ofautoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis,asthma, type I diabetes, inflammatory bowel disease, Crohn's disease,autoimmune thyroid disorders, Alzheimer's disease, nephritis), diseasesinvolving a hyperactive inflammatory response (e.g., eczema), allergies,lung diseases, cancer (e.g., prostate, breast, leukemia, multiplemyeloma), and some immune reactions (e.g., skin rash or contactdermatitis or diarrhea) caused by other therapeutics. The compounds,compositions, and methods described herein are directed toward theseneeds and others.

SUMMARY

The present invention provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables aredefined infra.

The present invention further provides compositions comprising acompound of the invention, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.

The present invention also provides methods of modulating an activity ofa PI3K kinase, comprising contacting the kinase with a compound of theinvention, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ina patient, wherein said disease is associated with abnormal expressionor activity of a PI3K kinase, comprising administering to said patient atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

The present invention further provides methods of treating animmune-based disease in a patient, comprising administering to saidpatient a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating a cancer in apatient, comprising administering to said patient a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof.

The present invention further provides methods of treating a lungdisease in a patient, comprising administering to said patient atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

The present invention also provides a compound of the invention, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for use in any of the methods described herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the crystal structure of the compound of Example 269.

DETAILED DESCRIPTION

The present invention provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is CR⁹ or N;

W is CR⁷ or N;

Y is CR⁸, CR^(8a), or N;

Z is a bond or C(═O);

provided that —W═Y—Z— is —CR⁷═CR⁸, —N═CR⁸—, —CR⁷═CR^(8a)—C(═O)—,—N═CR^(8a)—C(═O)—, or —CR⁷═N—C(═O)—;

R¹ is C₁₋₃ alkyl;

R² is halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,phenyl, or 5-6 membered heteroaryl; wherein said phenyl and 5-6 memberedheteroaryl are each optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, andC₁₋₄ haloalkoxy;

R³ is Cy, —(C₁₋₃ alkylene)-Cy, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted by 1, 2, 3, or4 independently selected R^(3a) groups;

R⁴ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁵ is halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyclopropyl;

R⁶ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁷ is H or C₁₋₄ alkyl;

R⁸ is H, halo, —OH, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), C(═NR^(e))R^(b2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), or S(═O)₂NR^(c2)R^(d2); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl are each optionallysubstituted by 1, 2, 3, or 4 independently selected R¹¹ groups;

R^(8a) is H, halo, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², C(═O)R^(b2), C(═O)NR^(c2)R^(d2),C(═O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), or S(═O)₂NR^(c2)R^(d2); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl are each optionallysubstituted by 1, 2, 3, or 4 independently selected R¹¹ groups;

R⁹ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R¹⁰ is H or C₁₋₄ alkyl;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 independently selected R^(3b) groups;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which isoptionally substituted with —OH or C₁₋₃ alkyl;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

each Cy is independently selected from C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, phenyl, naphthyl, and 5-10 membered heteroaryl, eachof which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3b) groups;

each R^(3a) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted with 1, 2, or 3 independently selectedR¹¹ groups;

each R^(3b) is independently selected from Cy¹, —(C₁₋₃ alkylene)-Cy¹,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)R^(b1), andS(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted with 1, 2, or 3 independently selectedR¹¹ groups;

each Cy¹ is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R¹¹groups;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 memberedheteroaryl are each optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups;

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which isoptionally substituted with —OH or C₁₋₃ alkyl;

each Cy² is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R¹¹groups;

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 memberedheteroaryl are each optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which isoptionally substituted with —OH or C₁₋₃ alkyl; and

each R¹¹ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

The present invention also provides, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is CR⁹ or N;

W is CR⁷ or N;

Y is CR⁸, CR^(8a), or N;

Z is a bond or C(═O);

provided that —W═Y—Z— is —CR⁷═CR⁸, —N═CR⁸—, —CR⁷═CR^(8a)—C(═O)—,—N═CR^(8a)—C(═O)—, or —CR⁷═N—C(═O)—;

R¹ is C₁₋₃ alkyl;

R² is halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,phenyl, or 5-6 membered heteroaryl; wherein said phenyl and 5-6 memberedheteroaryl are each optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, andC₁₋₄ haloalkoxy;

R³ is Cy, —(C₁₋₃ alkylene)-Cy, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted by 1, 2, 3, or4 independently selected R^(3a) groups;

R⁴ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁵ is halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyclopropyl;

R⁶ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁷ is H or C₁₋₄ alkyl;

R⁸ is H, halo, —OH, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), C(═NR^(e))R^(b2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), S(═O)₂R^(b2), orS(═O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, or 4 independently selectedR¹¹ groups;

R^(8a) is H, halo, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², C(═O)R^(b2), C(═O)NR^(c2)R^(d2),C(═O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), S(═O)₂R^(b2), orS(═O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, or 4 independently selectedR¹¹ groups;

R⁹ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R¹⁰ is H or C₁₋₄ alkyl;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 independently selected R^(3b) groups;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which isoptionally substituted with —OH or C₁₋₃ alkyl;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

each Cy is independently selected from C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, phenyl, naphthyl, and 5-10 membered heteroaryl, eachof which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3b) groups;

each R^(3a) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted with 1, 2, or 3 independently selectedR¹¹ groups;

each R^(3b) is independently selected from Cy¹, —(C₁₋₃ alkylene)-Cy¹,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)R^(b1),S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each Cy¹ is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R¹¹groups;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 memberedheteroaryl are each optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups;

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which isoptionally substituted with —OH or C₁₋₃ alkyl;

each Cy² is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, or 9-10-memberedbicyclic heteroaryl, each of which is optionally substituted with 1, 2,3, or 4 independently selected R¹¹ groups;

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 memberedheteroaryl are each optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which isoptionally substituted with —OH or C₁₋₃ alkyl; and

each R¹¹ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In an embodiment of either of the preceding embodiments, Cy is not

wherein:

G is NH, n is 1, and V is O; or

G is NH, n is 0, and V is O or CH₂; or

G is O, n is 0 and V is NH.

In an embodiments of the preceding embodiments, R³ is

In an embodiment of the preceding embodiments, R³ is Cy, wherein each Cyis independently selected from an azetidine ring, a pyrazole ring, apyridine ring, a pyrimidine ring, and a phenyl ring, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R3bgroups.

In some embodiments:

the

moiety is:

In some embodiments:

the

moiety is

In some embodiments:

the

moiety is

In some embodiments:

the

moiety is

In some embodiments:

the

moiety is

In some embodiments, R¹ is methyl.

In some embodiments, R² is C₁₋₆ alkyl, C₁₋₃ alkoxy, or phenyl; whereinsaid phenyl is optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from halo.

In some embodiments, each R^(a), R^(b), R^(c), and R^(d) isindependently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R³ is Cy or C(═O)NR^(c)R^(d); wherein each R^(c)and R^(d) is independently selected from C₁₋₆ alkyl.

In some embodiments, R³ is Cy.

In some embodiments, R³ is C(═O)NR^(c)R^(d); wherein each R^(c) andR^(d) is independently selected from C₁₋₆ alkyl.

In some embodiments, each Cy is independently selected from C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl, each of which is optionally substituted with 1, 2, 3, or 4independently selected R^(3b) groups.

In some embodiments, each Cy is independently selected from an azetidinering, a pyrazole ring, a pyridine ring, a pyrimidine ring, and a phenylring, each of which is optionally substituted with 1, 2, 3, or 4independently selected R^(3b) groups.

In some embodiments:

each Cy is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which isoptionally substituted with 1 or 2 R^(3b) independently selected fromCy¹, —(C₁₋₃ alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), andS(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, or 3 independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; and

each R¹¹ is independently OH or C₁₋₃ alkoxy.

In some embodiments:

each Cy is independently selected from an azetidine ring, a pyrazolering, a pyridine ring, a pyrimidine ring, a phenyl ring, each of whichis optionally substituted with one R^(3b) selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; and

each R¹¹ is independently OH or C₁₋₃ alkoxy.

In some embodiments:

each Cy is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which isoptionally substituted with 1 or 2 R^(3b) independently selected fromCy¹, —(C₁₋₃ alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), andS(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, or 3 independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments:

each Cy is independently selected from an azetidine ring, a pyrazolering, a pyridine ring, a pyrimidine ring, a phenyl ring, each of whichis optionally substituted with one R^(3b) selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments, R⁴ is halo, CN, or C₁₋₄ alkyl.

In some embodiments, R⁴ is F, Cl, CN, or methyl.

In some embodiments, R⁴ is F.

In some embodiments, R⁴ is Cl.

In some embodiments, R⁴ is CN.

In some embodiments, R⁴ is methyl

In some embodiments, R⁵ is halo or CN.

In some embodiments, R⁵ is Cl.

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is H.

In some embodiments, R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy²is selected from C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and4-7 membered heterocycloalkyl, each of which is optionally substitutedby 1 or 2 independently selected R¹¹ groups.

In some embodiments, R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy²is selected from C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, or4-7 membered heterocycloalkyl each of which is optionally substituted by1 R¹¹ selected from OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃ alkylcarbamyl, anddi(C₁₋₃ alkyl)carbamyl.

In some embodiments, R⁸ is H, halo, CN, methyl, or Cy²; wherein Cy² isselected from cyclopropyl, phenyl, a pyrazole ring, a pyridine ring, ora pyrimidine ring, each of which is optionally substituted by 1 R¹¹selected from OH, CN, fluoro, methyl, 2-hydroxyethyl, dimethylcarbamyl,amino, methylcarbamyl, and dimethylcarbamyl.

In some embodiments, R⁸ is H, methyl, F, Cl, or I.

In some embodiments, R⁸ is methyl.

In some embodiments, R⁸ is H.

In some embodiments, R⁸ is F.

In some embodiments, R⁸ is Cl.

In some embodiments, R⁸ is I.

In some embodiments, each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl,C₁₋₃ haloalkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments, R^(8a) is H, halo, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, or Cy².

In some embodiments, R^(8a) is H or halo.

In some embodiments, R^(8a) is H.

In some embodiments, R⁹ is H.

In some embodiments, R¹⁰ is H.

In some embodiments:

the

moiety is:

R¹ is methyl;

R² is C₁₋₆ alkyl, C₁₋₃ alkoxy, or phenyl; wherein said phenyl isoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo;

R³ is Cy or C(═O)NR^(c)R^(d); wherein each R^(c) and R^(d) isindependently selected from C₁₋₆ alkyl;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3b) groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN;

R⁶, R⁷, R⁹, and R¹⁰ are each H;

R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy² is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted by 1 or 2independently selected R¹¹ groups;

R^(8a) is H or halo; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments:

the

moiety is:

R¹ is methyl;

R² is C₁₋₆ alkyl, C₁₋₃ alkoxy, or phenyl; wherein said phenyl isoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo;

R³ is Cy or C(═O)NR^(c)R^(d); wherein each R^(c) and R^(d) isindependently selected from C₁₋₆ alkyl;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1 or 2 R^(3b) independently selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN;

R⁶, R⁷, R⁹, and R¹⁰ are each H;

R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy² is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted by 1 R¹¹group;

R^(8a) is H or halo; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments:

the

moiety is:

R¹ is methyl;

R² is C₁₋₃ alkoxy;

R³ is Cy;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3b) groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN;

R⁶, R⁷, R⁹, and R¹⁰ are each H;

R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy² is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted by 1 or 2independently selected R¹¹ groups;

R^(8a) is H or halo; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments:

the

moiety is:

R¹ is methyl;

R² is phenyl; wherein said phenyl is optionally substituted by 1, 2, 3,or 4 substituents independently selected from halo;

R³ is C(═O)NR^(c)R^(d); wherein each R^(c) and R^(d) is independentlyselected from C₁₋₆ alkyl;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3b) groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN;

R⁶, R⁷, R⁹, and R¹⁰ are each H;

R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy² is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted by 1 or 2independently selected R¹¹ groups;

R^(8a) is H or halo; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments:

the

moiety is:

R¹ is methyl;

R² is C₁₋₃ alkoxy;

R³ is Cy;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1 or 2 R^(3b) independently selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN;

R⁶, R⁷, R⁹, and R¹⁰ are each H;

R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy² is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted by 1 R¹¹group;

R^(8a) is H or halo; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments:

the

moiety is:

R¹ is methyl;

R² is phenyl; wherein said phenyl is optionally substituted by 1, 2, 3,or 4 substituents independently selected from halo;

R³ is C(═O)NR^(c)R^(d); wherein each R^(c) and R^(d) is independentlyselected from C₁₋₆ alkyl;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1 or 2 R^(3b) independently selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN;

R⁶, R⁷, R⁹, and R¹⁰ are each H;

R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy² is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted by 1 R¹¹group;

R^(8a) is H or halo; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments, the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula III:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula V:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula VIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula VIb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula VIa:

or a pharmaceutically acceptable salt thereof, wherein:

R² is methoxy or ethoxy;

R^(3b) is C₁₋₆ alkyl, optionally substituted by 1 or 2 groupsindependently selected from F, OH, and C₁₋₃ alkoxy groups;

R⁴ is F, CN, methyl or ethyl; and

R⁵ is F, Cl, methyl or ethyl.

In some embodiments, the compound is a compound of Formula VIb:

or a pharmaceutically acceptable salt thereof, wherein:

R² is methoxy or ethoxy;

R^(3b) is C(═O)NR^(c1)R^(d1);

R⁴ is F, CN, methyl or ethyl; and

R⁵ is F, Cl, methyl or ethyl.

In some embodiments, the compound is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

R² is C₁₋₆ alkyl, C₁₋₃ alkoxy, or phenyl; wherein said phenyl isoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo;

R³ is Cy or C(═O)NR^(c)R^(d); wherein each R^(c) and R^(a) isindependently selected from C₁₋₆ alkyl;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1 or 2 R^(3b) independently selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN;

R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy² is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted by 1 R¹¹group; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments, the compound is a compound of IIIa:

or a pharmaceutically acceptable salt thereof, wherein:

R² is C₁₋₆ alkyl, C₁₋₃ alkoxy, or phenyl; wherein said phenyl isoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo;

R³ is Cy or C(═O)NR^(c)R^(d); wherein each R^(c) and R^(d) isindependently selected from C₁₋₆ alkyl;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1 or 2 R^(3b) independently selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments, the compound is a compound of Formula IVa:

or a pharmaceutically acceptable salt thereof, wherein:

R² is C₁₋₆ alkyl, C₁₋₃ alkoxy, or phenyl; wherein said phenyl isoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo;

R³ is Cy or C(═O)NR^(c)R^(d); wherein each R^(c) and R^(d) isindependently selected from C₁₋₆ alkyl;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1 or 2 R^(3b) independently selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In some embodiments, the compound is a compound of Formula Va:

or a pharmaceutically acceptable salt thereof; wherein:

R² is C₁₋₆ alkyl, C₁₋₃ alkoxy, or phenyl; wherein said phenyl isoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo;

R³ is Cy or C(═O)NR^(c)R^(d); wherein each R^(c) and R^(d) isindependently selected from C₁₋₆ alkyl;

Cy is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, each of which is optionallysubstituted with 1 or 2 R^(3b) independently selected from Cy¹, —(C₁₋₃alkylene)-Cy¹, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C(═O)R^(b1), C(═O)NR^(c1)R^(d1), S(═O)R^(b1), and S(═O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo or CN;

R⁸ is H, halo, CN, C₁₋₆ alkyl, or Cy²; wherein Cy² is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted by 1 R¹¹group; and

each R¹¹ is independently OH, CN, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, or di(C₁₋₃ alkyl)carbamyl.

In the embodiments above for Formula IIa, IIIa, Iva or Va, R² is C₁₋₃alkoxy; and R³ is Cy.

In the embodiments above for Formula IIa, IIIa, Iva or Va, R² is phenyl;wherein said phenyl is optionally substituted by 1, 2, 3, or 4substituents independently selected from halo; and R³ isC(═O)NR^(c)R^(d); wherein each R^(c) and R^(d) is independently selectedfrom C₁₋₆ alkyl.

In any of the aforementioned embodiments, R² or R³ comprises at leastone cyclic moiety.

In some embodiments, the compound is selected from:

-   1-{1-[5-Chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-{1-[3-(1-Acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-propionylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-(1-{5-Chloro-3-[1-(cyclopropylmethyl)azetidin-3-yl]-2-methoxy-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-{1-[5-Chloro-3-(1-ethylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-{1-[5-Chloro-3-(1-isobutylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-{1-[3-(1-sec-butylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-(1-{5-Chloro-2-methoxy-3-[1-(2-methoxyethyl)azetidin-3-yl]-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylazetidine-1-carboxamide;-   5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[1-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-methylpicolinamide;-   4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)pyridine-2-carboxamide;-   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide;-   2-(4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl)ethanol;-   3′-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-N,N,6′-trimethylbiphenyl-4-carboxamide;-   3′-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-N,6′-dimethylbiphenyl-4-carboxamide;-   5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-(2-hydroxyethyl)picolinamide;-   4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide;-   5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   4-Amino-8-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)pyrido[2,3-d]pyrimidin-5(8H)-one;-   5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}nicotinonitrile;-   4-Amino-8-[1-(5-chloro-2-methoxy-4-methyl-3-pyridin-3-ylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one;-   4-Amino-8-[1-(5-chloro-2-methoxy-4-methyl-3-pyrimidin-5-ylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one;-   3′-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8    (5H)-yl)ethyl]-5′-chloro-2′-methoxy-N,N,6′-trimethylbiphenyl-3-carboxamide;-   4-Amino-8-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one;-   3′-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8    (5H)-yl)ethyl]-5′-chloro-2′-methoxy-N,N,6′-trimethylbiphenyl-3-sulfonamide;-   5-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylpyridine-2-carboxamide;-   4-Amino-8-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one;-   4-Amino-8-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one;-   5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   6-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-chloro-N-ethyl-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide;-   4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)pyridine-2-carboxamide;-   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-cyano-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide;-   5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile;-   5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-6-cyano-2-ethoxyphenyl)-N,N-dimethylpicolinamide;-   5-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide;-   4-(1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl)-6-chloro-3-ethoxy-2-(5-(methylsulfonyl)pyridin-3-yl)benzonitrile;-   5-(3-{1-[4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide;-   5-(3-{1-[4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide;-   5-(3-{1-[4-amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide;-   5-(3-{1-[4-amino-3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide;-   5-(3-{1-[4-amino-3-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide;-   5-[3-(1-{4-amino-3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[1-(4-amino-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[1-(4-amino-3-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   5-(3-{1-[4-amino-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide;-   5-{4-amino-1-[1-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-dimethylpyridine-2-carboxamide;-   5-(3-{1-[4-amino-3-(5-cyanopyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide;-   5-(3-{1-[4-amino-3-(2-aminopyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[1-(4-amino-3-{6-[(methylamino)carbonyl]pyridin-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[1-(4-amino-3-pyridin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[i-(4-amino-3-pyridin-3-yl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   5-{3-[1-(4-amino-3-{5-[(dimethylamino)carbonyl]pyridin-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;-   1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-oxetan-3-ylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   1-(1-{5-chloro-2-methoxy-4-methyl-3-[1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;-   5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylnicotinamide;    and-   5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;

or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments, the compound is selected from:

-   4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile;-   4-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile;-   4-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile;-   4-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile;-   4-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile;-   4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxyethyl)azetidin-3-yl)-3-methoxybenzonitrile;-   (S)-4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxyethyl)azetidin-3-yl)-3-methoxybenzonitrile;    and-   (R)-4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxyethyl)azetidin-3-yl)-3-methoxybenzonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments, the starred carbon in Formula I:

is a chiral carbon and said compound or said salt is the (S)-enantiomer.

In some embodiments, the compound is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

R² is methoxy, ethoxy, —OCHF₂, methyl, —F, or —CHF₂;

R⁴ is methyl, Cl, F, or CN; and

R⁵ is methyl, Cl, F, or CN.

In some embodiments, the compound is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

R² is methoxy, ethoxy, —OCHF₂, methyl, —F, or —CHF₂;

R⁴ is methyl, Cl, F, or CN;

R⁵ is methyl, Cl, F, or CN; and

R⁸ is H, halo, CN, methyl, or Cy²; wherein said Cy² is selected fromcyclopropyl, phenyl, a pyrazole ring, a pyridine ring, or a pyrimidinering, each of which is optionally substituted by 1 R¹¹ selected from OH,CN, fluoro, methyl, 2-hydroxyethyl, dimethylcarbamyl, amino,methylcarbamyl, and dimethylcarbamyl.

In some embodiments, the compound is a compound of Formula IIb:

or a pharmaceutically acceptable salt thereof, wherein:

R² is methoxy, ethoxy, —OCHF₂, methyl, —F, or —CHF₂;

R⁴ is methyl, Cl, F, or CN; and

R⁵ is methyl, Cl, F, or CN.

In some embodiments, the compound is a compound of Formula IIIa:

or a pharmaceutically acceptable salt thereof, wherein:

R² is methoxy, ethoxy, —OCHF₂, methyl, —F, or —CHF₂;

R⁴ is methyl, Cl, F, or CN; and

R⁵ is methyl, Cl, F, or CN.

In some embodiments, the compound is a compound of Formula IVa:

or a pharmaceutically acceptable salt thereof, wherein:

R² is methoxy, ethoxy, —OCHF₂, methyl, —F, or —CHF₂;

R⁴ is methyl, Cl, F, or CN; and

R⁵ is methyl, Cl, F, or CN.

In some embodiments, the compound is a compound of Formula Va:

or a pharmaceutically acceptable salt thereof, wherein:

R² is methoxy, ethoxy, —OCHF₂, methyl, —F, or —CHF₂;

R⁴ is methyl, Cl, F, or CN; and

R⁵ is methyl, Cl, F, or CN.

In some embodiments, the compound is a compound of Formula VIII:

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IX:

or pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment.

The present application further provides a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein:

G is NH, n is 1, and V is O; or

G is NH, n is 0, and V is O or CH₂; or

G is O, n is 0 and V is NH;

X is CR⁹ or N;

W is CR⁷ or N;

Y is CR⁸, CR^(8a), or N;

Z is a bond or C(═O);

provided that —W═Y—Z— is —CR⁷═CR⁸, —N═CR⁸—, —CR⁷═CR^(8a)—C(═O)—,—N═CR^(8a)—C(═O)—, or —CR⁷═N—C(═O)—;

R¹ is C₁₋₃ alkyl;

R² is halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,phenyl, or 5-6 membered heteroaryl; wherein said phenyl and 5-6 memberedheteroaryl are each optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, andC₁₋₄ haloalkoxy;

R⁴ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁵ is halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyclopropyl;

R⁶ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁷ is H or C₁₋₄ alkyl;

R⁸ is H, halo, —OH, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), C(═NR^(e))R^(b2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), S(═O)₂R^(b2), orS(═O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, or 4 independently selectedR¹¹ groups;

R^(8a) is H, halo, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², C(═O)R^(b2), C(═O)NR^(c2)R^(d2),C(═O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), S(═O)₂R^(b2), orS(═O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, or 4 independently selectedR¹¹ groups;

R⁹ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R¹⁰ is H or C₁₋₄ alkyl;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

each Cy² is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, or 9-10-memberedbicyclic heteroaryl, each of which is optionally substituted with 1, 2,3, or 4 independently selected R¹¹ groups;

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 memberedheteroaryl are each optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which isoptionally substituted with —OH or C₁₋₃ alkyl; and

each R¹¹ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In one embodiment, the compound of Formula VII is not the compounds ofExamples 310-311 and 323-325. In another embodiment, the compound ofFormula VII is selected from the compounds of Examples 310-311 and323-325.

In some embodiments, R¹ is methyl.

In some embodiments, R² is C₁₋₃ alkoxy.

In some embodiments, R⁴ is halo, CN, or C₁₋₄ alkyl.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁵ is halo.

In some embodiments, R⁵ is chloro or fluoro.

In some embodiments, R⁶ is H.

In some embodiments, R⁸ is C₁₋₆ alkyl.

In some embodiments, R⁸ is methyl.

In some embodiments, R¹⁰ is H.

In some embodiments, G is NH, n is 0 and V is O.

In some embodiments, G is NH, n is 0 and V is CH₂.

In some embodiments, G is NH, n is 1 and V is O.

In some embodiments, G is O, n is 0 and V is NH.

In some embodiments, the compound is a compound having Formula VIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound having Formula VIIb:

or a pharmaceutically acceptable salt thereof.

In some embodiments:

G is NH;

n is 0;

V is O;

R² is C₁₋₃ alkoxy;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo; and

R⁶ is H.

In some embodiments:

G is NH;

n is 0;

V is CH₂;

R² is C₁₋₃ alkoxy;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo; and

R⁶ is H.

In some embodiments:

G is NH;

n is 1;

V is O;

R² is C₁₋₃ alkoxy;

R⁴ is halo, CN, or C₁₋₄ alkyl;

R⁵ is halo; and

R⁶ is H.

In some embodiments:

G is O;

n is 0;

V is NH;

R² is C₁₋₃ alkoxy;

R⁴ is halo;

R⁵ is halo; and

R⁶ is H.

In some embodiments, the compound is selected from:

-   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}pyrrolidin-2-one;-   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile;-   6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}morpholin-3-one;-   5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-1,3-oxazolidin-2-one;-   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one;-   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile;-   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one;    and-   5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one,

or a pharmaceutically acceptable salt thereof of any of theaforementioned.

In some embodiments, the compound is selected from:

-   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one;-   (S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;-   (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;-   (S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;    and-   (R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof of any of theaforementioned.

In some embodiments, the starred carbon in Formula VII:

is a chiral carbon and said compound or salt is the (S)-enantiomer.

Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.Examples of alkyl moieties include, but are not limited to, chemicalgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl,3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. In someembodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “alkylene”, employed alone or in combinationwith other terms, refers to a divalent alkyl linking group. Examples ofalkylene groups include, but are not limited to, ethan-1,2-diyl,propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl,butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy),t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6,1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “cyano-C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-OH.

As used herein, the term “C₁₋₃ alkoxy-C₁₋₃ alkyl” refers to a group offormula —(C₁₋₃ alkylene)-O(C₁₋₃ alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments,the halo group is F or Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In some embodiments, the haloalkoxy group is fluorinated only. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, or 7ring-forming carbons (C₃₋₇). Ring-forming carbon atoms of a cycloalkylgroup can be optionally substituted by oxo or sulfido. Cycloalkyl groupsalso include cycloalkylidenes. Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, and the like. In some embodiments,cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Alsoincluded in the definition of cycloalkyl are moieties that have one ormore aromatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo or thienyl derivatives ofcyclopentane, cyclohexane, and the like. A cycloalkyl group containing afused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring.

A five-membered heteroaryl ring is a heteroaryl with a ring having fivering atoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary five-membered ringheteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl with a ring having sixring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary six-membered ringheteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl andpyridazinyl.

A “bicyclic C₉₋₁₀ heteroaryl” is bicyclic fused heteroaryl having 9 to10 ring members.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkylgroups can also include spirocycles. Example heterocycloalkyl groupsinclude pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl,tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, andthe like. Ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally substituted by oxo or sulfido(e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group canbe attached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or thienyl derivatives of piperidine, morpholine,azepine, etc. A heterocycloalkyl group containing a fused aromatic ringcan be attached through any ring-forming atom including a ring-formingatom of the fused aromatic ring. In some embodiments, theheterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatomsindependently selected from nitrogen, oxygen or sulfur and having one ormore oxidized ring members.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached any ring member provided that thevalency of the atom is not exceeded. For example, an azetidine ring maybe attached at any position of the ring, whereas an azetidin-3-yl ringis attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

In some embodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999), which is incorporated herein by referencein its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

For example, compounds of Formula I can be formed as shown in Scheme I.The compound (i) can be halogenated with N-chlorosuccinamide,N-bromosuccinamide or N-iodosuccinamide to give compound (ii) whereX¹=Cl, Br, or I. The halo group of (ii) can be coupled to R³-M, where Mis a boronic acid, boronic ester or an appropriately substituted metal(e.g., R³-M is R³—B(OH)₂, R³—Sn(Bu)₄, or Zn—R³), under standard Suzukiconditions or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., a bicarbonate or carbonate base) or standard Negishiconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative offormula (iii). Alternatively, R³-M can be a cyclic amine (where M is Hand attached to the amine nitrogen) with coupling to compound (ii) beingperformed by heating in base or under Buchwald conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford ketone (iii). Reduction of the ketone (iii) with asuitable reagent, such as sodium tetrahydroborate can furnish thealcohol (iv) which can be converted to a derivative bearing a leavinggroup (v), (e.g., Lg is chloride via reaction with cyanuric chloride ormesylate via reaction with methanesulfonic anhydride). Finally, compound(v) can be reacted with an appropriate heterocycle (vi) (e.g.,3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine or4-aminopyrido[2,3-d]pyrimidin-5(8H)-one) under basic conditions (e.g.,NaH or CsCO₃ or K₂CO₃) to give a compound of Formula I (vii).

Alternatively, compounds of Formula I can also be formed as shown inScheme II. The ketone compound (i) can be halogenated withN-chlorosuccinamide, N-bromosuccinamide or N-iodosuccinamide to givecompound (ii) where X¹=Cl, Br, or I. Ketone (ii) can be reduced with asuitable reagent, such as sodium tetrahydroborate, to give an alcohol(iii) which can be converted to a derivative bearing a leaving group,(e.g., Lg is chloride via reaction with cyanuric chloride or mesylatevia reaction with methanesulfonic anhydride) and then reacted with aheterocycle to give a heterocyclic derivative (iv). The enantiomers ofcompound (iv) can be separated by chiral chromatography to afford asingle enantiomer of heterocyclic compound (v). Finally, the halo groupof (v) can be coupled to R³-M, where M is a boronic acid, boronic esteror an appropriately substituted metal (e.g., R³-M is R³—B(OH)₂,R³—Sn(Bu)₄, or Zn—R³), under standard Suzuki conditions or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., abicarbonate or carbonate base) or standard Negishi conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula I (vi).

Compounds of Formula I, wherein L is O, N, or S, can be formed as shownin Scheme III. The thiols, phenols or amines (i) can be alkylated usingMitsunobu conditions (e.g., R′OH, DEAD, Ph₃P) or standard alkylatingconditions (R′-Lg, Lg=leaving group) to afford thioether, ether, oralkylamine derivatives (ii), respectively. The halo group of (ii) can becoupled to R³-M, where M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., R³-M is R³—B(OH)₂, R³—Sn(Bu)₄, orZn—R³) under standard Suzuki conditions or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative offormula (iii). Alternatively, R³-M can be a cyclic amine (where M is Hand attached to the amine nitrogen) with coupling to compound (ii) beingperformed by heating in base or under Buchwald conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)-palladium(0) and a base (e.g., an alkoxidebase)) to afford compounds of formula (iii). The ketone (iii) can betransformed using similar methods as shown in Scheme I and II to affordcompounds of Formula I (iv). Alternatively, the halo-ketone (ii) can betransformed using similar methods as shown in Scheme I and II to affordhalo intermediate (v). Suzuki, Stille, Negishi or Buchwald coupling ofR³-M with halo intermediate (v) by similar methods described in SchemesI and II can also afford compounds of Formula I (vi).

Compounds of Formula I can be formed as shown in Scheme IV. Compound (i)can be acylated with a suitable acylating reagent (e.g., R¹—COCl) toform an ester which can be rearranged under Lewis acid conditions e.g.,BF₃/HOAc complex) to afford ketone (ii). Halogenation of ketone (ii)using NX¹S (e.g., NX¹S=N-chlorosuccinamide, N-bromosuccinamide orN-iodosuccinamide) can give compound (iii) where X¹=Cl, Br, or I. Thephenol can be converted to the triflate (iv) using standard conditions(e.g., Tf₂O). The triflate group of (iv) can be coupled to R³-M, where Mis a boronic acid, boronic ester or an appropriately substituted metal(e.g., R³-M is R³—B(OH)₂, R³—Sn(Bu)₄, or Zn—R³) under standard Suzukiconditions or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., a bicarbonate or carbonate base) or standard Negishiconditions (e.g., in the presence a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative offormula (v). Alternatively, R²-M can be a cyclic amine (where M is H andattached to the amine nitrogen) with coupling to compound (iv) beingperformed by heating in base or under Buchwald conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford ketone (v). The halo group of (v) can be coupled toR³-M, where M is a boronic acid, boronic ester or an appropriatelysubstituted metal (e.g., R³-M is R³—B(OH)₂, R³—Sn(Bu)₄, or Zn—R³), understandard Suzuki conditions or standard Stille conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base)) to give a derivative of formula (vi). Alternatively,R³-M can be a cyclic amine (where M is H and attached to the aminenitrogen) with coupling to compound (iv) being performed by heating inbase or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)) to afford ketone (vi). The ketone(vi) can be transformed using similar methods as shown in Scheme I andII to afford compounds of Formula I (viii).

Alternatively, the halo-ketone (v) can be transformed using similarmethods as shown in Scheme I and II to afford halo intermediate (vii).Suzuki, Stille, Negishi or Buchwald coupling of M-R³ with compound (vii)by similar methods described in Schemes I and II can also affordcompounds of Formula I (viii).

Ketones which can be used in the processes of Scheme I, II and III canbe formed as shown in Scheme V below. The carboxylic acid (i) can beactivated with a coupling agent (e.g., HBTU, HATU or EDC) and thenreacted with N,O-dimethylhydroxylamine to give aN-methoxy-N-methylcarboxamide derivative (ii). Amide (ii) may then bereacted with a Grignard reagent of formula R¹—MgX¹ (X¹=halo) to give aketone (iii). The ketone (iii) can be transformed using similar methodsas shown in Scheme I, II and III to afford compounds of Formula I.

Ketones which can be used in the processes of Scheme I, II and III, canalso be formed as shown in Scheme VI below. The carboxylic acid (i) canbe activated with a coupling agent (e.g. HBTU or HATU) and then reactedwith N,O-dimethylhydroxylamine to give a N-methoxy-N-methylcarboxamide.The thiols, phenols or amines can be alkylated using Mitsunobuconditions (e.g., R′OH, DEAD, Ph₃P) or standard alkylating conditions(R′-Lg, Lg=leaving group) to afford thioether, ether or alkylaminederivatives (ii), respectively. The halo group of (ii) (X¹ is halo) canbe coupled to R³-M, where M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., R³-M is R³—B(OH)₂, R³—Sn(Bu)₄, orZn—R³), under standard Suzuki conditions or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative offormula (iii). Alternatively, R³-M can be a cyclic amine (where M is Hand attached to the amine nitrogen) with coupling to compound (ii) beingperformed by heating in base or under Buchwald conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford amides (iii). Reaction of compound (iii) with aGrignard reagent of formula R¹—MgX² (X²=halo) can give ketone (iv). Theketone (iv) can be transformed using similar methods as shown in SchemeI, II and III to afford compounds of Formula I.

Compounds which can be used in the processes of Schemes I-III can alsobe formed as shown in Scheme VII. The halo-ketone (i) (X¹ is halo) canbe converted to the cyano-ketone (ii) using standard cyanationconditions (e.g., Pd(O) and Zn(CN)₂). Hydrolysis of the cyano group of(ii) under acid or base conditions can give the carboxylic acid whichcan be coupled to amines using a coupling agent (e.g., HATU, HBTU, EDC)and appropriate amines (HNR^(c)R^(d)) to give amide (iii). In someembodiments, R^(c) and R^(d), along with the nitrogen atom to which theyare attached can optionally cyclize to form a 4-7 memberedheterocycloalkyl group (thereby providing compounds wherein R³ isC(O)R^(b), wherein R^(b) is 4-7 membered heterocycloalkyl). The ketoneof amide (iii) can be transformed using similar methods as shown inScheme I, II and III to afford compounds of Formula I.

Additional compounds which can be used in the processes of Schemes I-IIIcan be formed as shown in Scheme VIII. The ketone (i) can be convertedto the nitro-ketone (ii) using standard nitration conditions (e.g.,HNO₃). Reduction of the nitro group of (ii) under standard conditions(e.g., Fe, Zn, H₂ over Pd/C) can give the amino compound which can beacylated with appropriate acylating agents (e.g., RC═OCl, ROC═OCl,SO₂Cl, RRNC═O) to give ketone (iii). The ketone (iii) can be transformedusing similar methods as shown in Scheme I, II and III to affordcompounds of Formula I. In some embodiments, R^(c) and R^(d), along withthe nitrogen atom to which they are attached can optionally cyclize toform a 4-7 membered heterocycloalkyl group (thereby providing compoundswherein R³ is C(O)R^(b), wherein R^(b) is 4-7 memberedheterocycloalkyl).

Ketones which can be used in the processes of Scheme I, II and III, canalso be formed as shown in Scheme IX below. The halo group (e.g., X¹=I)of (i) can be coupled to a zinc reagent R³—Zn (e.g., such as tert-butyl3-iodoazetidine-1-carboxylate with Zn dust) under standardKnochel/Negishi conditions (e.g., in the presence of a palladium(0)catalyst, such as tri-(2-furyl)phosphine andtris(dibenzylideneacetone)dipalladium(0) and 1,2-dibromoethane andchlorotrimethylsilane) to give a derivative of formula (ii). Theazetidine (ii) can be deprotected (e.g., Pg=Boc, using TFA) and thenreacted under alkylating, acylating or reductive amination (e.g., RXsuch as R—Br, RCOCl, R—SO₂Cl, RN═C═O or RCHO and a reducing agent)conditions to afford ketone derivatives (iii) which can be converted tocompounds of Formula I (v) by similar methods shown in Schemes I, II,and III). Alternatively, the ketone (ii) can be reduced with suitablereagents (NaBH₄ or Corey's chiral CBS catalyst to give predominantly oneisomer of the alcohol), the resulting alcohol can be converted to aleaving group (e.g., Lg is chloride via reaction with cyanuric chlorideor mesylate via reaction with methanesulfonic anhydride) and then thechloride or mesylate reacted with an appropriate heterocycle (e.g.,similar to methods shown in Schemes I, II and III) to afford derivativesof formula (iv). The protecting group on the amine can be removed understandard conditions and then reacted under alkylating, acylating orreductive amination conditions (e.g., RX such as R—Br, RCOCl, R—SO₂Cl,RN═C═O or RCHO and a reducing agent) to give compounds of Formula I (v).

Compounds of Formula I can also be formed as shown in Scheme X. Thecompound (i) can be reacted with a halo-substituted heterocycle (ii)(e.g., 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine or4-amino-6-iodopyrido[2,3-d]pyrimidin-5(8H)-one) under basic conditions(e.g., NaH or CsCO₃ or K₂CO₃) to give compound (iii) where V=Cl, Br, orI. The halo group of (iii) can be coupled to R³-M, where M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., R⁸-M isR⁸—B(OH)₂, R⁸—Sn(Bu)₄, or Zn—R⁸), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative offormula (iii). Alternatively, R⁸-M can be a cyclic amine (where M is Hand attached to the amine nitrogen) with coupling to compound (iii)being performed by heating in base or under Buchwald conditions (e.g.,in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford compounds of Formula I (iv).

Compounds of Formula I can also be formed as shown in Scheme XI. Cyanoderivative (i) can be hydrolyzed to the acid (e.g. in the presence ofacid or base) to give the corresponding acid (ii). The carboxylic acid(ii) can be coupled to an amine (e.g., HNR^(c2)R^(d2) is dimethylamine)(iii) using appropriate coupling agents (e.g. HATU, HBTU, EDC) in thepresence of a base, such as TEA or DIEA to give the amide (iii). Thecarboxylic acid (ii) can also be reduced to the alcohol (iv) whereR^(t)=H with an appropriate reducing agent (e.g. LAH or NaBH₄) orconverted to the ester and reacted with a Grignard reagent (e.g.R^(t)MgBr) or an alkyllithium (e.g. R^(t)Li) to give the secondary ortertiary alcohols (iv). The alcohol (iv) can be activated by convertingto a leaving group, such as a halide by reacting with suitable reagents,such as cyanuric chloride, and then reacted with an appropriate amine(e.g. HNR^(c2)R^(d2)) to give compounds of Formula I (v). Alternatively,the alcohol (iv) can be reacted under Mitsunobu conditions (e.g. in thepresence of DEAD, triphenylphosphine and a compound A (e.g. a phenol orheteroaryl bearing an NH, e.g. imidazole) to give compounds of Formula I(vi). Other modifications would be readily apparent to one of skill inthe art, starting from the compounds depicted in Scheme XI (e.g.,esterification of alcohols, etc.).

Compound of Formula I can be synthesized from an acid chloride compound(i) as illustrated in Scheme XII. Condensation of an acid chloride (i)with malononitrile in the presence of a base, such as sodium hydride,can give a dicyanoenol intermediate, which can be O-methylated with anappropriate reagent, such as dimethyl sulfate in the presence of anappropriate base, such as sodium bicarbonate, to yield an enol ether(ii). Reaction of enol ether (ii) with hydrazine dihydrochloride in thepresence of a suitable base, such as triethylamine, can give a pyrazolecompound (iii). Pyrazole compound (iii) can then be reacted withformamide to give pyrazolopyrimidine (iv). Finally, compound (iv) can bereacted with appropriate compound bearing a leaving group (v) underbasic conditions to give a compound of Formula I (vi).

Compounds of Formula I can be synthesized from commercially available4-aminopyrido[2,3-d]pyrimidine-5(8H)-one (i). Halogenation of compound(i) with suitable reagents, such as N-halo succinamide (NX¹S, whereX¹=Cl, Br or I) can give the corresponding halo compound (ii). Reactionof the halo derivative (ii) with a compound (iii) bearing a leavinggroup in the presence of a suitable base (e.g. diisopropylethylamine)can give compound (iv). The halo compound (iv) can be coupled toR^(8a)-M, where M is a boronic acid, boronic ester or an appropriatelysubstituted metal (e.g., R^(8a)-M is R^(8a)—B(OH)₂, R^(8a)—Sn(Bu)₄, orZn—R^(8a)), under standard Suzuki conditions or standard Stilleconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative offormula (iii). Alternatively, R^(8a)-M can be a cyclic amine (where M isH and attached to the amine nitrogen) with coupling to compound (iii)being performed by heating in base or under Buchwald conditions (e.g.,in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford compounds of Formula I (v).

Compounds of Formula I can also be formed as shown in Scheme XIV. Thehalo group, X¹, of (i) can be coupled to an alkene (e.g., acrylate oracrylamide) under standard Heck conditions (e.g., in the presence of apalladium(II) catalyst, such as palladium acetate) to give an alkene offormula (ii). Reaction of alkene (ii) with nitromethane in the presenceof DBU can afford the nitro derivative (iii) which can be reduced understandard conditions (e.g., NiCl₂/NaBH₄) to give a free amine whichcyclizes to form lactam (iv). The lactam can be alkylated under standardconditions (e.g., R^(3a)—X², where X²=halo, in the presence of a base,such as TEA or NaH) to give an N-alkyl-lactam (v). Compounds of formula(v), and pyrrolidines derived from the reduction of the lactam (v) withsuitable reducing agents, such as LiAlH₄, can be converted to compoundsof Formula I using conditions described in Schemes I, II and III.

Compounds of Formula I can also be formed as shown in Scheme XV. Thehalo group X¹ of (i) can be coupled to R³-M, where M is an appropriatelysubstituted metal (e.g., R³-M is R³B(OH)₂; appropriate non-limitingstarting materials for generating R³-M are shown in Scheme XII) understandard Suzuki conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0)) to give analkene of formula (ii). Epoxidation of alkene (ii) with mCPBA can affordthe epoxide (iii) which can be reacted with a secondary or primary amine(amine=NHR^(c)R^(d); R^(c)=H for primary amine) to give amino compoundsof formula (iv). Secondary or tertiary amine derivatives (iv) can befurther reacted with carbonyldiamidazole or phosgene to form anoxazolidinone (v) or an acetyl-halide (e.g., chloro-acetylchloride inthe presence of base, such as TEA) to give the N-acyl derivative whichcan be converted to the morpholinone derivative (vi) upon treatment witha base (e.g., NaH). Compounds of formula (iv, v, and vi) can bedeprotected using standard conditions (e.g., compounds protected withTHP groups may be treated with an acid, such as TFA or HCl) to givecompounds of Formula I.

Compounds of Formula I can also be formed as shown in Scheme XVI.Sharpless amino-hydroxylation of an alkene of formula (i) under suitableconditions (A or B, as described in JACS, 2001, 123(9), 1862-1871 and J.Org. Chem, 2011, 76, 358-372) can give either amino-hydroxy isomer (ii)or (iii). Compounds (ii) and (iii) can be reacted withcarbonyldiamidazole or phosgene to form an oxazolidinone (iv), or anacetyl-halide (e.g., chloro-acetylchloride in the presence of base, suchas TEA) to give an N-acyl derivative which can be converted to themorpholinone derivative (v) upon treatment with a base (e.g., NaH). Thealternate amino-hydroxy isomer (iii) can be converted to oxazolidinoneand morpholinone derivatives as shown in Scheme XV.

Compounds of Formula I can be synthesized as shown in Scheme XVII. Thehalo group (e.g., X¹=Cl, Br, I) of (i) can be converted to the boronateester (ii) under standard conditions (e.g., pinnacle boronate ester inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)). Boronate (ii) can be reactedwith an arylhalide or heteroarylhalide (e.g., R³—X²) under Suzukiconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base, such as Na₂CO₃) togive formula (iii). Formula (iii) can be converted to Formula I usingthe reaction conditions described in Schemes I, II or III.

Compounds of Formula I, where R⁴=F or CN, can be formed as shown inScheme XVIII. Compound (i) can be acylated with a suitable acylatingreagent (e.g., R¹—COCl) to form an ester which can be rearranged underLewis acid conditions (e.g., BF₃/HOAc complex) to afford ketone (ii).Ketone (ii) can be halogenated with N-chlorosuccinamide,N-bromosuccinamide or N-iodosuccinamide to give phenol (iii), whereX¹=Cl, Br, or I. Compound (iii) can be alkylated (e.g. R²—X and a base,such as NaH or Na₂CO₃; or under Mitsunobu conditions) to afford theether (iv). The fluoro group of (iv) can be displaced (e.g., with NaCNor KCN) to give cyano derivative (v). The halo group of (v) can becoupled to R³-M, where M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., R³-M is R³—B(OH)₂, R³—Sn(Bu)₄, orZn—R³), under standard Suzuki conditions or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)), to give a derivative offormula (vi). Alternatively, R³-M can be a cyclic amine (where M is Hand attached to the amine nitrogen) and coupled to compound (v) byheating in base or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)) to afford ketone (vi). Reduction ofthe ketone (vi) with a suitable reagent, such as sodium tetrahydroborateor the Corey CBS reagent can furnish the alcohol which can be convertedto a derivative bearing a leaving group, (e.g., Lg is chloride viareaction with cyanuric chloride or mesylate via reaction withmethanesulfonic anhydride) and then reacted with an appropriateheterocycle (e.g., 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine or4-aminopyrido[2,3-d]pyrimidin-5(8H)-one) under basic conditions (e.g.,NaH or CsCO₃ or K₂CO₃) to give a compound of Formula I (viii).Alternatively, the last two steps can be inverted so that the ketone (v)can be reduced to give an alcohol which is converted to a leaving groupand displaced with the heterocycle first and then the Suzuki, Stille,Negishi or Buchwald coupling is performed to give compounds of Formula I(viii). The fluoro derivatives (iv) can also be converted to compoundsof Formula I by eliminating the cyanation step in scheme XVIII.

Compounds of Formula I can also be formed as shown in Scheme XIX.Compound (i) can be acylated with a suitable acylating reagent (e.g.,R¹—COCl) to form an ester which can be rearranged under Lewis acidconditions (e.g., AlCl₃ or BF₃/HOAc complex) to afford ketone (ii).Halogenation of ketone (ii) using NX¹S (e.g., NX¹S=N-chlorosuccinamide,N-bromosuccinamide or N-iodosuccinamide) can give compound (iii), whereX¹=Cl, Br, or I. The phenol can be converted to an ether (iv) usingstandard conditions (e.g., inorganic base, such as K₂CO₃, and an alkylhalide, such as Et-I). The halo group of (iv) can be coupled to R³-M,where M is a boronic acid, boronic ester or an appropriately substitutedmetal (e.g., R³-M is R³—B(OH)₂, R³—Sn(Bu)₄, or Zn—R³ and R³ is asubstituted or unsubstituted olefin, such as vinyl) under standardSuzuki conditions or standard Stille conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) to give a derivative of formula (v). The alkene canthen be dihydroxylated using Sharpless conditions to afford the diol(vi). Enhancement of one enantiomer of the secondary alcohol can beachieved using standard Sharpless asymmetric dihydroxylation methods.The secondary alcohol can be converted to the N-Boc protected amine viaa 6 step process (e.g. silyl protection (e.g., TBS-Cl and DIEA) of theprimary alcohol, mesylation of the secondary alcohol, displacement ofthe mesylate with NaN₃, reduction of the azide with Ph₃P, Boc protectionof the resulting primary amine and then deprotection of the silylprotecting group on the primary alcohol with TBAF) to affordamino-alcohol (vii). The amino-alcohol (vii) can be converted into theoxazolidinone by treatment with phosgene and subsequent reduction of theketone with a suitable reagent, such as sodium tetrahydroborate orsodium borohydride can furnish the alcohol (viii) which can be convertedto a derivative bearing a leaving group (ix) (e.g., Lg is chloride viareaction with cyanuric chloride or mesylate via reaction withmethanesulfonic anhydride). Finally, compound (ix) can be reacted withan appropriate heterocycle (x) (e.g.,3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine or4-aminopyrido[2,3-d]pyrimidin-5(8H)-one) under basic conditions (e.g.,NaH or Cs₂CO₃ or K₂CO₃) to give a compound of Formula I (xi).

Methods

The compounds of the invention can modulate activity of one or more ofvarious kinases including, for example, phosphoinositide 3-kinases(PI3Ks). The term “modulate” is meant to refer to an ability to increaseor decrease the activity of one or more members of the PI3K family.Accordingly, the compounds of the invention can be used in methods ofmodulating a PI3K by contacting the PI3K with any one or more of thecompounds or compositions described herein. In some embodiments,compounds of the present invention can act as inhibitors of one or morePI3Ks. In further embodiments, the compounds of the invention can beused to modulate activity of a PI3K in an individual in need ofmodulation of the receptor by administering a modulating amount of acompound of the invention, or a pharmaceutically acceptable saltthereof. In some embodiments, modulating is inhibiting.

Given that cancer cell growth and survival is impacted by multiplesignaling pathways, the present invention is useful for treating diseasestates characterized by drug resistant kinase mutants. In addition,different kinase inhibitors, exhibiting different preferences in thekinases which they modulate the activities of, may be used incombination. This approach could prove highly efficient in treatingdisease states by targeting multiple signaling pathways, reduce thelikelihood of drug-resistance arising in a cell, and reduce the toxicityof treatments for disease.

Kinases to which the present compounds bind and/or modulate (e.g.,inhibit) include any member of the PI3K family. In some embodiments, thePI3K is PI3Kα, PI3Kβ, PI3Kγ, or PI3Kδ. In some embodiments, the PI3K isPI3Kγ or PI3Kδ. In some embodiments, the PI3K is PI3Kγ. In someembodiments, the PI3K is PI3Kδ. In some embodiments, the PI3K includes amutation. A mutation can be a replacement of one amino acid for another,or a deletion of one or more amino acids. In such embodiments, themutation can be present in the kinase domain of the PI3K.

In some embodiments, more than one compound of the invention is used toinhibit the activity of one kinase (e.g., PI3Kγ or PI3Kδ).

In some embodiments, more than one compound of the invention is used toinhibit more than one kinase, such as at least two kinases (e.g., PI3Kγand PI3Kδ).

In some embodiments, one or more of the compounds is used in combinationwith another kinase inhibitor to inhibit the activity of one kinase(e.g., PI3Kγ or PI3Kδ).

In some embodiments, one or more of the compounds is used in combinationwith another kinase inhibitor to inhibit the activities of more than onekinase (e.g., PI3Kγ or PI3Kδ), such as at least two kinases.

The compounds of the invention can be selective. By “selective” is meantthat the compound binds to or inhibits a kinase with greater affinity orpotency, respectively, compared to at least one other kinase. In someembodiments, the compounds of the invention are selective inhibitors ofPI3Kγ or PI3Kδ over PI3Kα and/or PI3Kβ. In some embodiments, thecompounds of the invention are selective inhibitors of PI3Kδ (e.g., overPI3Kα, PI3Kβ and PI3Kγ). In some embodiments, the compounds of theinvention are selective inhibitors of PI3Kγ (e.g., over PI3Kα, PI3Kβ andPI3Kδ). In some embodiments, selectivity can be at least about 2-fold,5-fold, 10-fold, at least about 20-fold, at least about 50-fold, atleast about 100-fold, at least about 200-fold, at least about 500-foldor at least about 1000-fold. Selectivity can be measured by methodsroutine in the art. In some embodiments, selectivity can be tested atthe K_(m) ATP concentration of each enzyme. In some embodiments, theselectivity of compounds of the invention can be determined by cellularassays associated with particular PI3K kinase activity.

Another aspect of the present invention pertains to methods of treatinga kinase (such as PI3K)-associated disease or disorder in an individual(e.g., patient) by administering to the individual in need of suchtreatment a therapeutically effective amount or dose of one or morecompounds of the present invention or a pharmaceutical compositionthereof. A PI3K-associated disease can include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the PI3K, including overexpression and/or abnormal activitylevels. In some embodiments, the disease can be linked to Akt (proteinkinase B), mammalian target of rapamycin (mTOR), orphosphoinositide-dependent kinase 1 (PDK1). In some embodiments, themTOR-related disease can be inflammation, atherosclerosis, psoriasis,restenosis, benign prostatic hypertrophy, bone disorders, pancreatitis,angiogenesis, diabetic retinopathy, atherosclerosis, arthritis,immunological disorders, kidney disease, or cancer. A PI3K-associateddisease can also include any disease, disorder or condition that can beprevented, ameliorated, or cured by modulating PI3K activity. In someembodiments, the disease is characterized by the abnormal activity ofPI3K. In some embodiments, the disease is characterized by mutant PI3K.In such embodiments, the mutation can be present in the kinase domain ofthe PI3K.

Examples of PI3K-associated diseases include immune-based diseasesinvolving the system including, for example, rheumatoid arthritis,allergy, asthma, glomerulonephritis, lupus, or inflammation related toany of the above.

Further examples of PI3K-associated diseases include cancers such asbreast, prostate, colon, endometrial, brain, bladder, skin, uterus,ovary, lung, pancreatic, renal, gastric, or hematological cancer.

In some embodiments, the hematological cancer is acute myeloblasticleukemia (AML) or chronic myeloid leukemia (CML), or B cell lymphoma.

Further examples of PI3K-associated diseases include lung diseases suchas acute lung injury (ALI) and adult respiratory distress syndrome(ARDS).

Further examples of PI3K-associated diseases include osteoarthritis,restenosis, atherosclerosis, bone disorders, arthritis, diabeticretinopathy, psoriasis, benign prostatic hypertrophy, inflammation,angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease,myasthenia gravis, multiple sclerosis, or Sjögren's syndrome, and thelike.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a PI3K with a compound of the invention includesthe administration of a compound of the present invention to anindividual or patient, such as a human, having a PI3K, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the PI3K.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician. In some embodiments, the dosage ofthe compound, or a pharmaceutically acceptable salt thereof,administered to a patient or individual is about 1 mg to about 2 g,about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg toabout 100 mg, about 1 mg to 50 mg, or about 50 mg to about 500 mg.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing a disease,condition or disorder in an individual who may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease; (2) inhibiting thedisease; for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology); and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

Combination Therapies

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, EGFR, HER2, JAK (e.g.,JAK1 or JAK2), c-MET, VEGFR, PDGFR, cKit, IGF-1R, RAF, FAK, Akt mTOR,PIM, and AKT (e.g., AKT1, AKT2, or AKT3) kinase inhibitors such as, forexample, those described in WO 2006/056399, or other agents such as,therapeutic antibodies can be used in combination with the compounds ofthe present invention for treatment of PI3K-associated diseases,disorders or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present invention and are presented as a non limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa,Tarceva, antibodies to EGFR, Gleevec™, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine,cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine,Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP,MDL-101,731, and bendamustine (Treanda).

Example chemotherapeutics include proteosome inhibitors (e.g.,bortezomib), thalidomide, revlimid, and DNA-damaging agents such asmelphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include coriticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include the compounds, and pharmaceuticallyacceptable salts thereof, of the genera and species disclosed in U.S.Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 03/037347, WO03/099771, and WO 04/046120.

Example suitable RAF inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO05/028444.

Example suitable FAK inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 04/080980, WO04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.

Example suitable mTOR inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 2011/025889.

In some embodiments, the compounds of the invention can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the invention can be used incombination with a chemotherapeutic in the treatment of cancer, such asmultiple myeloma, and may improve the treatment response as compared tothe response to the chemotherapeutic agent alone, without exacerbationof its toxic effects. Examples of additional pharmaceutical agents usedin the treatment of multiple myeloma, for example, can include, withoutlimitation, melphalan, melphalan plus prednisone [MP], doxorubicin,dexamethasone, and Velcade (bortezomib). Further additional agents usedin the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAKkinase inhibitors. Additive or synergistic effects are desirableoutcomes of combining a PI3K inhibitor of the present invention with anadditional agent. Furthermore, resistance of multiple myeloma cells toagents such as dexamethasone may be reversible upon treatment with thePI3K inhibitor of the present invention. The agents can be combined withthe present compound in a single or continuous dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of theinvention where the dexamethasone is administered intermittently asopposed to continuously.

In some further embodiments, combinations of the compounds of theinvention with other therapeutic agents can be administered to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable. Thisinvention also includes pharmaceutical compositions which contain, asthe active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the invention contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the invention.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating PI3K in tissue samples,including human, and for identifying PI3K ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes PI3Kassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F,³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro PI3K labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or willgenerally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, one or more H atomsfor any compound described herein is each replaced by a deuterium atom.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a PI3K by monitoring its concentrationvariation when contacting with the PI3K, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a PI3K (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the PI3Kdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of PI3K-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be PI3Kinhibitors according to at least one assay described herein.

EXAMPLES

The example compounds below containing one or more chiral centers wereobtained in racemate form or as isomeric mixtures, unless otherwisespecified. Salt stoichiometry which is indicated any of the productsbelow is meant only to indicate a probable stoichiometry, and should notbe construed to exclude the possible formation of salts in otherstoichiometries. The abbreviations “h” and “min” refer to hour(s) andminute(s), respectively.

Example 1.1-{1-[5-Chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

Step 1. 1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone

To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone(from Oakwood, 50.0 g, 271 mmol) in acetic acid (300 mL) was addedN-iodosuccinimide (73.1 g, 325 mmol) and the resulting mixture wasstirred on a heating mantle between 60˜80° C. over 3.5 hours then cooledto room temperature and stirred overnight. Water (500 mL) was added tothe mixture in portions, which caused a dark solid to form. Afterstirring for 10 minutes, the solids were filtered, washing withadditional water. The light to dark brown solids were dried under vacuumfor 4 hours then air dried over the weekend to give 81.3 g (97%) of thedesired product. LCMS calculated for C₉H₉ClIO₂ (M+H)⁺: m/z=310.9; Found:311.0. ¹H NMR (300 MHz, CDCl₃): δ 13.21 (s, 1H), 7.71 (s, 1H), 2.65 (s,3H), 2.63 (s, 3H) ppm.

Step 2. 1-(5-Chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone

Potassium carbonate (72.4 g, 524 mmol) was added to a mixture of1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (81.3 g, 262 mmol)and methyl iodide (19.6 mL, 314 mmol) in N,N-dimethylformamide (250 mL).The mixture was stirred at room temperature for 4 hours. Water (500 mL)was added and stirred for 15 minutes. The dark solids were filtered anddried in vacuo to give 42.3 g of the desired product. The filtrate wasextracted with EtOAc (4×). The combined filtrates were washed with water(2×) and brine, dried (MgSO₄), filtered and concentrated. The solidswere dried in vacuo to give an additional 37.2 g of the desired product.The product was used without further purification. LCMS calculated forC₁₀H₁₁ClIO₂ (M+H)⁺: m/z=324.9; Found: 325.0. ¹H NMR (300 MHz, CDCl₃): δ7.62 (s, 1H), 3.78 (s, 3H), 2.65 (s, 3H), 2.62 (s, 3H) ppm.

Step 3. tert-Butyl3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

Zinc (1.71 g, 26.2 mmol) was suspended in N,N-dimethylformamide (45.0mL) and 1,2-dibromoethane (210 μL, 2.5 mmol) was added. The mixture washeated at 60° C. for 10 minutes and then cooled to room temperature.Chlorotrimethylsilane (330 μL, 2.6 mmol) was added and stirred at 60° C.for 10 minutes and cooled to room temperature. A solution of tert-butyl3-iodoazetidine-1-carboxylate (from Oakwood, 6.25 g, 22.1 mmol) inN,N-dimethylformamide (5.0 mL) was then added and the mixture stirred atroom temperature for 1 hour.1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (5.00 g, 15.4mmol), tri-(2-furyl)phosphine (358 mg, 1.54 mmol), andtris(dibenzylideneacetone)dipalladium(0) (0.70 g, 0.77 mmol) were addedin order and the reaction mixture was warmed to 70° C. and stirredovernight. The mixture was cooled to room temperature and partitionedbetween ethyl acetate (EtOAc) and sat. NH₄Cl solution. The layers wereseparated and the aqueous extracted further with EtOAc (2×). Thecombined organics were washed with water and brine, dried over MgSO₄,and concentrated. The residue was purified on silica gel, eluting with0-30% EtOAc in hexanes to give 3.0 g (55%) of the desired product as anorange solid. LCMS calculated for C₁₈H₂₄ClNO₄Na (M+Na)⁺: m/z=376.1;Found: 376.0. ¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 4.32, (m, 2H),4.16 (m, 3H), 3.66 (s, 3H), 2.59 (s, 3H), 2.31 (s, 3H), 1.45 (s, 9H)ppm.

Step 4. tert-Butyl3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate

To a solution of tert-butyl3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(1.3 g, 3.7 mmol) in methanol (20 mL) stirring at 0° C. was added sodiumtetrahydroborate (0.167 g, 4.41 mmol). The mixture was stirred at 0˜5°C. for 1 hour. The reaction was quenched with water and extracted withEtOAc (3×). The combined extracts were dried over MgSO₄, filtered andconcentrated to give 1.3 g (100%) of the desired product. LCMScalculated for C₁₈H₂₆ClNO₄Na (M+Na)⁺: m/z=378.2; Found: 378.1. ¹H NMR(400 MHz, CDCl₃): δ 7.37 (s, 1H), 5.10 (q, 1H), 4.30 (m, 2H), 4.14 (m,3H), 3.63 (s, 3H), 2.25 (s, 3H), 1.48 (d, 3H), 1.44 (s, 9H) ppm.

Step 5. tert-Butyl3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate

Cyanuric chloride (from Aldrich, 1.22 g, 6.62 mmol) was weighed into aflask and N,N-dimethylformamide (0.512 mL, 6.62 mmol) was added. Afterstirring for a few minutes a solution of tert-butyl3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate(1.5 g, 4.2 mmol) in methylene chloride (30 mL) was added. The resultingmixture was stirred at room temperature overnight. Water was added, andthen diluted with dichloromethane. The layers were separated and theorganics were washed with sat. NaHCO₃ solution, water, brine, dried overMgSO₄, and concentrated. The resulting residue was purified on silicagel, eluting with 0-35% EtOAc in hexanes to give the desired product(1.36 g, 86%). LCMS calculated for C₁₃H₁₇ClNO (M-Cl-Boc+H)⁺: m/z=238.1;Found: 238.1. ¹H NMR (400 MHz, CDCl₃): δ 7.46 (s, 1H), 5.44, (q, 1H),4.32 (m, 2H), 4.18-4.10 (m, 3H), 3.67 (s, 3H), 2.27 (s, 3H), 1.79 (d,3H), 1.44 (s, 9H) ppm.

Step 6. tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate

At room temperature, sodium hydride (0.32 g, 8.0 mmol) was added to asuspension of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (fromChemBridge, 0.59 g, 4.0 mmol) in N,N-dimethylformamide (20 mL). Theresulting mixture was stirred at room temperature for 25 minutes duringwhich time the suspension became a nearly clear solution. To theresultant mixture was added a solution of tert-butyl3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate(1.35 g, 3.61 mmol, from Example 1, step 5) in N,N-dimethylformamide (10mL). The mixture was stirred at 50° C. overnight. After cooling, themixture was diluted with water and extracted with EtOAc (2×). Thecombined extracts were washed with water and brine, dried over MgSO₄ andconcentrated. The resulting residue was purified on silica gel, elutedwith 0-10% MeOH in dichloromethane to give 1.03 g (59%) of the desiredproduct as a yellow gum. The racemic products were applied on aPhenomenex Lux-Cellulose 2 column (21.1×250 mm, 5 micron particle size),eluting with 10% ethanol in hexanes at a flow rate of 18 mL/min, 4mg/injection, to provide two enantiomers. The retention time of thefirst peak was 8.34 min and the retention time for the second peak was10.92 min. Peak 1 (463 mg), LCMS calculated for C₂₄H₃₂ClN₆O₃ (M+H)⁺:m/z=487.2; Found: 487.1. ¹H NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 7.37(s, 1H), 6.30, (q, 1H), 5.40 (s, 2H), 4.23 (m, 2H), 4.17˜4.00 (m, 3H),3.57 (s, 3H), 2.58 (s, 3H), 2.16 (s, 3H), 1.76 (d, 3H), 1.37 (s, 9H)ppm.

Step 7.1-[1-(3-Azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

To a solution of tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate(318 mg, 0.653 mmol) (peak 1 from above) in methylene chloride (3.2 mL)was added 4.0 M hydrogen chloride in 1,4-dioxane (1.6 mL, 6.5 mmol). Theresulting mixture was stirred at room temperature for 75 minutes. Thesolvents were evaporated and the residue dried in vacuo to give 0.30 gof the desired product as the bis-HCl salt. LCMS calculated forC₁₉H₂₄ClN₆O (M+H)⁺: m/z=387.2; Found: 387.1.

Step 8.1-{-[5-Chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (58 mg, 0.13 mmol), acetone (18.5 μL, 0.252 mmol) andtriethylamine (54.5 μL, 0.391 mmol) in methylene chloride (1.0 mL) wasadded resin of sodium triacetoxyborohydride (108 mg, 0.249 mmol). Theresulting mixture was stirred for 3 hours at room temperature. Themixture was filtered and concentrated. The crude product was purifiedusing RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive 50 mg (60%) of the desired product as the TFA salt. LCMS calculatedfor C₂₂H₃₀ClN₆O (M+H)⁺: m/z=429.2; Found: 429.1. The product wasisolated as a single enantiomer. ¹H NMR (500 MHz, DMSO-d₆): δ 8.47 (s,1H), 7.46 (s, 1H), 6.29 (q, J=6.9 Hz, 1H), 4.52 (m, 2H), 4.21 (m, 1H),4.15 (t, J=9.8 Hz, 1H), 4.06 (t, J=9.7 Hz, 1H), 3.53 (s, 3H), 3.39˜3.27(m, 1H), 2.61 (s, 3H), 2.11 (s, 3H), 1.75 (d, J=6.8 Hz, 3H), 1.11 (dd,J=6.0, 3.8 Hz, 6H) ppm.

Example 2.1-{1-[3-(1-Acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

Step 1.1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

To a solution of the racemic tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate(146 mg, 0.300 mmol) (racemic intermediate from Example 1 Step 6) inmethylene chloride (1.5 mL) was added 4.0 M hydrogen chloride in1,4-dioxane (0.75 mL, 3.0 mmol). After stirred at rt for 2 h, thesolvents were evaporated and the resulting residue dried in vacuo togive 138 mg of the desired product as the HCl salt. LCMS calculated forC₁₉H₂₄ClN₆O (M+H)⁺: m/z=387.2; Found: 387.1.

Step 2.1-{1-[3-(1-Acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (20.0 mg, 0.0435 mmol, from Example 2, step 1) andtriethylamine (30.3 μL, 0.217 mmol) in methylene chloride (0.20 mL) wasadded acetyl chloride (6.18 μL, 0.0870 mmol). The resulting mixture wasstirred overnight at room temperature. The solvents were evaporated andthe crude purified using RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30mL/min) to give the desired product as the TFA salt. The product wasisolated as a racemic mixture. LCMS calculated for C₂₁H₂₆ClN₆O₂ (M+H)⁺:m/z=429.2; Found: 429.1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (s, 1H), 7.34(s, 1H), 6.26 (q, 1H), 4.50 (m, 1H), 4.28˜4.20 (m, 2H), 4.01 (m, 1H),3.88 (m, 1H), 3.52 (s, 3H), 2.58 (s, 3H), 2.18 (s, 3H), 1.75˜1.71 (m,6H) ppm.

Example 3.1-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-propionylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

This compound was prepared using procedures analogous to those forExample 2, with propanoyl chloride instead of acetyl chloride. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₂H₂₈ClN₆O₂ (M+H)⁺: m/z=443.2; Found: 443.2. ¹H NMR (400 MHz, DMSO-d₆)δ 8.30 (s, 1H), 7.33 (s, 1H), 6.25 (q, 1H), 4.49 (m, 1H), 4.27˜4.18 (m,2H), 4.02 (m, 1H), 3.90 (m, 1H), 3.54 (s, 3H), 2.57 (s, 3H), 2.18 (s,3H), 2.05 (q, 2H), 1.72 (d, 3H), 0.93 (t, 3H) ppm.

Example 4.1-(1-{5-Chloro-3-[1-(cyclopropylmethyl)azetidin-3-yl]-2-methoxy-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

This compound was prepared using procedures analogous to those forExample 1, with racemic1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride from Example 2, Step 1 and cyclopropanecarboxaldehyde(from Aldrich) instead of acetone. The product was isolated as a racemicmixture. LCMS calculated for C₂₃H₃₀ClN₆O (M+H)⁺: m/z=441.2; Found:441.1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.06 (s, 1H), 7.13 (s, 1H), 5.96 (q,1H), 4.22 (m, 2H), 4.07 (m, 1H), 3.90 (m, 1H), 3.80 (m, 1H), 3.24 (s,3H), 2.68 (t, 2H), 2.21 (s, 3H), 1.80 (s, 3H), 1.45 (d, 3H), 0.64 (m,1H), 0.24 (m, 2H), 0.01 (m, 2H) ppm.

Example 5.1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

This compound was prepared using procedures analogous to those forExample 1, with racemic1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride from Example 2, Step 1 and formaldehyde instead ofacetone. The crude purified using RP-HPLC (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₀H₂₆ClN₆O (M+H)⁺: m/z=401.2; Found: 401.2.

Example 6.1-{1-[5-Chloro-3-(1-ethylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

This compound was prepared using procedures analogous to those forExample 1, with racemic1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride from Example 2, Step 1 and acetaldehyde instead ofacetone. The crude purified using RP-HPLC (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₁H₂₈ClN₆O (M+H)⁺: m/z=415.2; Found: 415.1.

Example 7.1-{1-[5-Chloro-3-(1-isobutylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

This compound was prepared using procedures analogous to those forExample 1, with racemic1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride from Example 2, Step 1 and isobutyraldehyde instead ofacetone. The crude purified using RP-HPLC (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₃H₃₂ClN₆O (M+H)⁺: m/z=443.2; Found: 443.1. ¹H NMR (400 MHz, CDCl₃): δ8.29 (s, 1H), 7.38 (s, 1H), 6.37 (q, 1H), 5.37 (s, 2H), 4.01 (m, 2H),3.87 (m, 1H), 3.57 (s, 3H), 3.05 (t, 1H), 2.86 (t, 1H), 2.64 (s, 3H),2.18 (d, 2H), 2.11 (s, 3H), 1.82 (d, 3H), 1.62 (m, 1H), 0.89 (d, 6H)ppm.

Example 8.1-{1-[3-(1-sec-butylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

This compound was prepared using procedures analogous to those forExample 1, with racemic1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride from Example 2, Step 1 and 2-butanone instead ofacetone. The crude was purified using RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. Theproduct was isolated as a mixture of diastereomers. LCMS calculated forC₂₃H₃₂ClN₆O (M+H)⁺: m/z=443.2; Found: 443.1.

Example 9.1-(1-{5-Chloro-2-methoxy-3-[1-(2-methoxyethyl)azetidin-3-yl]-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

This compound was prepared using procedures analogous to those forExample 1, with racemic1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride from Example 2, Step 1 and methoxyacetaldehyde insteadof acetone. The crude was purified using RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₂H₃₀ClN₆O₂ (M+H)⁺: m/z=445.2; Found: 445.2.

Example 10.3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylazetidine-1-carboxamide

This compound was prepared using procedures analogous to those forExample 2, with methyl isocyanate instead of acetyl chloride The crudepurified using RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product. The product was isolated as aracemic mixture. LCMS calculated for C₂₁H₂₇ClN₇O₂ (M+H)⁺: m/z=444.2;Found: 444.2.

Example 11.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

Step 1. 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone

To a stirred solution of 1-(5-chloro-2-methoxy-4-methylphenyl)ethanone(5.00 g, 25.2 mmol, from Oakwood) in acetic acid (100 mL) was addedN-bromosuccinimide (4.93 g, 27.7 mmol) and the resulting mixture heatedat 100° C. for 18 hours. After cooling to ambient temperature, thereaction mixture was concentrated in vacuo, then neutralized with sat.sodium bicarbonate, filtered off insoluble succinimide. The filtrate wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over sodium sulfate, and then concentrated to dryness underreduced pressure. The residue was purified on silica gel, eluting with 0to 50% EtOAc in hexanes, to give the desired products (2.66 g, 38%).LCMS calculated for C₁₀H₁₁BrClO₂ (M+H)⁺: m/z=277.0; found: 277.0. ¹H NMR(DMSO-d₆, 300 MHz): δ 7.70 (1H, s), 3.77 (3H, s), 2.57 (3H, s), 2.50(3H, s) ppm.

Step 2.5-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

To a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone(0.38 g, 1.4 mmol) andN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(from PepTech, 0.46 g, 1.6 mmol) in 1,4-dioxane (6 mL), potassiumcarbonate (0.38 g, 2.7 mmol) in water (2 mL) was added. The reactionmixture was bubbled with N₂. Tetrakis(triphenylphosphine)palladium(0)(0.095 g, 0.082 mmol) was added and the reaction was stirred overnightat 100° C. The reaction was diluted with water, extracted with EtOAc.The combined organic layers were dried over MgSO₄, concentrated andpurified on silica gel (eluting with 0-100% EtOAc in hexanes) to givethe desired product. LCMS calculated for C₁₈H₂₀ClN₂O₃ (M+H)⁺: m/z=347.1;Found: 347.1.

Step 3.5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

To a solution of5-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide(106 mg, 0.306 mmol) in methanol (2 mL) cooled at 0° C. was added sodiumtetrahydroborate (14 mg, 0.37 mmol). The mixture was stirred at roomtemperature for 1 hour, then quenched with water, extracted with EtOAc.The organic layers were dried over MgSO₄ and concentrated to give crudealcohol. LCMS calculated for C₁₈H₂₂ClN₂O₃ (M+H)⁺: m/z=349.1; Found:349.1.

Step 4.5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Cyanuric chloride (85 mg, 0.46 mmol) was added to N,N-dimethylformamide(0.036 mL, 0.46 mmol) at room temperature. After the formation of awhite solid (10 minutes), methylene chloride (2 mL) was added, followedby5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(115 mg, 0.330 mmol, from Example 11, step 3). After the addition, themixture was stirred at room temperature overnight. Water was added, andthen diluted with dichloromethane. The organic phase was washed withsat. NaHCO₃ solution, water and brine, then dried over MgSO₄,concentrated. The residue was purified on silica gel (eluting with 0 to80% EtOAc in hexanes) to give the desired product (76 mg, 63%). LCMScalculated for C₁₈H₂₁Cl₂N₂O₂ (M+H)⁺: m/z=367.1; Found: 367.0.

Step 5.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6.1 mg,0.041 mmol) in N,N-dimethylformamide (0.4 mL) was added sodium hydride(60%, 2.0 mg, 0.082 mmol) at 0° C. and the mixture was stirred at roomtemperature for 10 minutes. To the resultant mixture was added asolution of5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(15.0 mg, 0.0408 mmol) in N,N-dimethylformamide (0.2 mL). The mixturewas stirred at room temperature overnight. The crude mixture waspurified on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive the desired product as bis-TFA salt. The product was isolated as aracemic mixture. LCMS calculated for C₂₄H₂₇ClN₇O₂ (M+H)⁺: m/z=480.2;Found: 480.1.

Example 12.5-{3-[1-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidetrifluoroacetate

To a mixture of 7H-pyrrolo[2,3-d]pyrimidin-4-amine sulfate (fromOakwood, 20 mg, 0.086 mmol), cesium carbonate (42 mg, 0.13 mmol) andpotassium iodide (1.4 mg, 0.0086 mmol) in N,N-dimethylformamide (0.91mL) was added5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(32 mg, 0.086 mmol) and the resulting mixture was stirred at 140° C. for1 hour. The mixture was diluted with methanol and purified on RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 30 mL/min) to give the desiredproduct. The product was isolated as a racemic mixture. LCMS calculatedfor C₂₄H₂₆ClN₆O₂ (M+H)⁺: m/z=465.2; Found: 465.1.

Example 13.1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

Step 1. 1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone

To 4-chloro-3-fluorophenol (from Aldrich, 20 g, 100 mmol) was addedacetyl chloride (14.1 mL, 199 mmol) under N₂ with stirring. Theresulting mixture turned into a clear solution at room temperaturequickly and it was heated at 60° C. for 2 hours. To the resultantmixture was added aluminum trichloride (25.0 g, 187 mmol) in portionsand the reaction mixture was heated at 180° C. for 30 minutes. Thesolids slowly dissolved at high temperature. The reaction mixture wasthen cooled to room temperature while the flask was swirled carefully inorder for the solid to form a thin layer inside the flask and thenslowly quenched with 1.0 N HCl (300 mL) while cooling in an ice-bath andstirred overnight. The yellow precipitate was washed with water anddried under vacuum to give the desired product as a yellow solid (23.8g), which was directly used in the next step without furtherpurification.

Step 2. 1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone

A solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (23.8 g, 126mmol) in acetic acid (100 mL) was treated with N-iodosuccinimide (34.1g, 151 mmol) and stirred at 70° C. for 2 hr. The reaction mixture wasconcentrated, diluted with EtOAc and quenched with sat. NaHCO₃ solutionuntil the bubbling stopped. The organic layers were separated, washedwith water, dried over MgSO₄ and stripped to give the desired productwhich was used in the next step without further purification.

Step 3. 1-(5-Chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone

1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (13 g, 41 mmol) wasdissolved in N,N-dimethylformamide (41.3 mL). Methyl iodide (3.9 mL, 62mmol) was added followed by potassium carbonate (11 g, 83 mmol). Thereaction was heated at 60° C. for 1 hour. The mixture was cooled to roomtemperature, diluted with ether. The organic layers were separated andcombined, washed with water, dried over MgSO₄, concentrated and purifiedon silica gel (eluting with 0 to 10% EtOAc in hexanes) to give thedesired product (10 g, 70%). LCMS calculated for C₉H₈ClFIO₂ (M+H)⁺:m/z=328.9; Found: 328.9.

Step 4. tert-Butyl3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate

Zinc (0.682 g, 10.4 mmol) was suspended with 1,2-dibromoethane (0.0598mL, 0.694 mmol) in N,N-dimethylformamide (12 mL). The mixture was heatedat 70° C. for 10 minutes and then cooled to room temperature.Chlorotrimethylsilane (0.088 mL, 0.69 mmol) was added dropwise andstirring was continued for 1 hour. A solution of tert-butyl3-iodoazetidine-1-carboxylate (2.5 g, 8.7 mmol) in N,N-dimethylformamide(10 mL) was then added and the mixture was heated at 40° C. for 1 hourbefore a mixture of 1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone(3.0 g, 9.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.16 g,0.17 mmol) and tri-(2-furyl)phosphine (0.081 g, 0.35 mmol) inN,N-dimethylformamide (20 mL) was added. The reaction mixture was warmedto 70° C. and stirred overnight. The mixture was then cooled to roomtemperature and partitioned between ether and sat. NH₄Cl solution. Theorganic layers were washed with water, dried over MgSO₄, concentratedand purified on silica gel (eluting with 0 to 25% EtOAc in hexanes) togive the desired product (0.8 g). LCMS calculated for C₁₇H₂₁ClFNO₄Na(M+Na)⁺: m/z=380.1; Found: 380.1.

Step 5. tert-Butyl3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate

To a solution of tert-butyl3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate(0.17 g, 0.48 mmol) in methanol (3 mL) cooled at 0° C. was added sodiumtetrahydroborate (0.022 g, 0.57 mmol). The mixture was stirred at roomtemperature for 1 hour, then quenched with water, extracted with EtOAc.The organic layers were combined, dried over MgSO₄ and concentrated togive the crude alcohol (0.19 g). LCMS calculated for C₁₇H₂₃ClFNO₄Na(M+Na)⁺: m/z=382.1; Found: 382.0.

Step 6. tert-Butyl3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate

Cyanuric chloride (140 mg, 0.78 mmol) was added to N,N-dimethylformamide(0.059 mL, 0.77 mmol) at room temperature. After the formation of awhite solid (ca. 10 minutes), methylene chloride (4 mL) was added,followed by tert-butyl3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate(197 mg, 0.547 mmol). After addition, the mixture was stirred at roomtemperature overnight. Water was added, and then diluted withdichloromethane. The organic phases were washed with sat. NaHCO₃solution, water and brine, dried over MgSO₄, and concentrated. Theresulting residue was purified on silica gel (eluting with 0 to 30%EtOAc in hexanes) to give the desired product (110 mg, 53%).

Step 7. tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate

To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.9 mg,0.053 mmol) in N,N-dimethylformamide (0.6 mL) was added sodium hydride(60%, 2.5 mg, 0.11 mmol) at 0° C. and the mixture was stirred at roomtemperature for 10 minutes. To the mixture was added a solution oftert-butyl3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate(20 mg, 0.053 mmol) in N,N-dimethylformamide (0.3 mL). The reactionmixture was stirred at 35° C. overnight, then quenched with water,extracted with ether. The combined organic layers were dried over MgSO₄and concentrated to afford the desired product which was used in nextstep directly. LCMS calculated for C₂₃H₂₉ClFN₆O₃ (M+H)⁺: m/z=491.2;Found: 491.1.

Step 8.1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

A mixture of tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate(14 mg, 0.028 mmol) in methylene chloride (0.2 mL) was treated with 4.0M hydrogen chloride in dioxane (0.2 mL, 0.8 mmol) at room temperaturefor 1 hour and then the solvent removed to give1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amineHCl salt. To a mixture of the crude HCl salt in acetonitrile (0.1mL)/methanol (0.1 mL)/tetrahydrofuran (0.1 mL) was addedN,N-diisopropylethylamine (0.1 mL, 0.6 mmol), followed by acetone (0.050mL, 0.68 mmol). The mixture was stirred for 30 minutes before theaddition of sodium triacetoxyborohydride (0.030 g, 0.14 mmol). Thereaction was stirred at room temperature overnight, then quenched andpurified on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive the desired product as TFA salt. The product was isolated as aracemic mixture. LCMS calculated for C₂₁H₂₇ClFN₆O (M+H)⁺: m/z=433.2;Found: 433.1.

Example 14.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

Step 1. 1-(5-Chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone

1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (18.9 g, 60.9 mmol)(from Example 1, Step 1) was dissolved in N,N-dimethylformamide (60.8mL). Iodoethane (7.3 mL, 91 mmol) was added followed by potassiumcarbonate (17 g, 120 mmol). The reaction was heated at 60° C. for 1hour. The mixture was cooled to room temperature, diluted with ether.The organic layers were combined, washed with water, dried over MgSO₄,concentrated and purified on silica gel (eluting with 0-10% EtOAc inhexanes) to give the desired product (18.9 g, 91.7%). LCMS calculatedfor C₁₁H₁₃ClIO₂ (M+H)⁺: m/z=339.0; Found: 339.0.

Step 2.5-(3-Acetyl-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

To a mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone(0.69 g, 2.0 mmol) andN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(0.68 g, 2.4 mmol) in 1,4-dioxane (10 mL), potassium carbonate (0.56 g,4.1 mmol) in water (3 mL, 200 mmol) was added. The reaction was bubbledwith N₂. Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol)was added and N₂ was bubbled. Reaction was stirred overnight at 95° C.The reaction was diluted with water, extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, concentrated and purified onsilica gel (eluting with 0 to 90% EtOAc in hexanes) to give the desiredproduct (0.6 g, 82%). LCMS calculated for C₁₉H₂₂ClN₂O₃ (M+H)⁺:m/z=361.1; Found: 361.0.

Step 3.5-[3-Chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

To a solution of5-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide(0.60 g, 1.7 mmol) in methanol (10 mL) cooled at 0° C. was added sodiumtetrahydroborate (0.075 g, 2.0 mmol). The mixture was stirred at roomtemperature for 1 hour, then quenched with water, extracted with EtOAc.The extracts were dried over MgSO₄ and concentrated to give crudealcohol (0.6 g). LCMS calculated for C₁₉H₂₄ClN₂O₃ (M+H)⁺: m/z=363.1;Found: 363.0.

Step 4.5-[3-Chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Cyanuric chloride (0.43 g, 2.3 mmol) was added to N,N-dimethylformamide(0.18 mL, 2.3 mmol) at room temperature. After the formation of a whitesolid (10 minutes), methylene chloride (10 mL) was added, followed by5-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(0.6 g, 2 mmol). After addition, the mixture was stirred at roomtemperature overnight, then diluted with dichloromethane and washed withsat. NaHCO₃ solution. The organic layers were dried over MgSO₄,concentrated. The residue was purified on silica gel (eluting with 0 to50% EtOAc in hexanes) to give the desired product (0.58, 90%). LCMScalculated for C₁₉H₂₃Cl₂NO₂ (M+H)⁺: m/z=381.1; Found: 381.0.

Step 5.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (47 mg,0.31 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride(60%, 12.6 mg, 0.524 mmol) at 0° C. and the resultant mixture wasstirred at room temperature for 10 minutes. To the mixture was added asolution of5-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(100 mg, 0.3 mmol, from Example 14, step 4) in N,N-dimethylformamide (1mL). The reaction was stirred at 35° C. overnight. The reaction wasquenched and applied on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30mL/min) to give the desired product as bis-TFA salt. The product wasisolated as a racemic mixture. LCMS calculated for C₂₅H₂₉ClN₇O₂ (M+H)⁺:m/z=494.2; Found: 494.1.

Example 15.5-{3-[1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

To a mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from CNHTechnologies, 120 mg, 0.46 mmol), cesium carbonate (200 mg, 0.62 mmol)and potassium iodide (7.0 mg, 0.042 mmol) in N,N-dimethylformamide (1mL) was added5-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(160 mg, 0.42 mmol, from Example 14, step 4) and the mixture was stirredat 140° C. for 1 hour. The reaction mixture was diluted with water,extracted with ether. The combined organic layers were dried over MgSO₄,concentrated and purified on silica gel (eluting with 0 to 10% MeOH indichloromethane) to give the desired product (0.12 g, 47%). The productwas isolated as a racemic mixture. LCMS calculated for C₂₄H₂₆ClIN₇O₂(M+H)⁺: m/z=606.1; Found: 606.0.

Example 16.4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Step 1. 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol

Sodium tetrahydroborate (0.31 g, 8.1 mmol) was added to a mixture of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (from Example 11,Step 1) (1.5 g, 5.4 mmol) in methanol (25 mL) at 0° C. and the resultantreaction mixture was stirred at room temperature for 1 hour. The solventwas removed and the resulting residue was diluted with ethyl acetate,washed with sat. NaHCO₃, water, brine, then dried over Na₂SO₄, filteredand concentrated. The crude product was purified by silica gelchromatography, eluting with 0 to 40% EtOAc in hexanes (0.30 g, 90%).

Step 2.4-[3-Chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile

A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (0.30g, 1.1 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile(from Combi-Blocks, 0.27 g, 1.2 mmol), sodium carbonate (230 mg, 2.1mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (100 mg, 0.13 mmol) in acetonitrile(8 mL)/water (2 mL) was degassed and then refilled with N₂. The reactionwas stirred at 95° C. for 2 hours, then cooled and diluted with ethylacetate, washed with sat. NaHCO₃, water, brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by silica gelchromatography, eluting with 0 to 40% EtOAc in hexanes (0.249 g, 75%).LCMS calculated for C₁₆H₁₆ClN₂O₂ (M+H)⁺: m/z=303.1; Found: 303.0.

Step 3.4-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile

A mixture of cyanuric chloride (170 mg, 0.94 mmol) andN,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperaturefor 10 minutes and then a solution of4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile(190 mg, 0.628 mmol) in methylene chloride (4 mL) was added and thereaction was stirred at room temperature overnight. The mixture wasdiluted with methylene chloride, washed with sat. NaHCO₃, water, brine,dried over Na₂SO₄, filtered and concentrated. The crude product was useddirectly in the next step without purification (121 mg, 60%). LCMScalculated for C₁₆H₁₅Cl₂N₂O (M+H)⁺: m/z=321.0; Found: 321.0.

Step 4.4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile

Sodium hydride (20 mg, 0.50 mmol) was added to a mixture of4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile(90 mg, 0.28 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (63 mg,0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirredet 30° C. overnight. The mixture was cooled, treated with water and thenfiltered to provide the desired product. LCMS calculated for C₂₂H₂₁ClN₇O(M+H)⁺: m/z=434.1; Found: 434.2.

Step 5.4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylicacid

Sodium hydroxide (1.0 M) in water (0.70 mL, 0.70 mmol) was added to amixture of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile(0.060 g, 0.14 mmol) in ethanol (1.0 mL) and the resultant mixture washeated at 95° C. for 6 hours. At this time, conc. HCl was added toadjust pH to ˜3. The solvent was removed and the residue was used in thenext step without further purification. LCMS calculated for C₂₂H₂₂ClN₆O₃(M+H)⁺: m/z=453.1; Found: 453.2.

Step 6.4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

2.0 M Dimethylamine in THF (0.14 mL, 0.28 mmol) was added to a solutionof4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylicacid (9.6 mg, 0.021 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperaturefollowed by addition of triethylamine (8.8 μL, 0.064 mmol). The reactionwas stirred for 1 hour. The crude mixture was purified using RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to givethe desired product. The product was isolated as a racemic mixture. LCMScalculated for C₂₄H₂₇ClN₇O₂ (M+H)⁺: m/z=480.2; Found: 480.2.

Example 17.4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-methylpicolinamide

This compound was prepared using procedures analogous to those forExample 16, Step 6, with 2.0 M solution of methylamine in THF replacing2.0 M dimethylamine in THF. The product was isolated as a racemicmixture. LCMS calculated for C₂₃H₂₅ClN₇O₂ (M+H)⁺: m/z=466.2; Found:466.2.

Example 18.4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)pyridine-2-carboxamide

This compound was prepared using procedures analogous to those forExample 16, Step 6, with ethanolamine replacing 2.0 M dimethylamine inTHF. The product was isolated as a racemic mixture. LCMS calculated forC₂₄H₂₇ClN₇O₃ (M+H)⁺: m/z=496.2; Found: 496.2.

Example 19.4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide

This compound was prepared using procedures analogous to those forExample 16, Step 6, with 2-(methylamino)ethanol replacing 2.0 Mdimethylamine in THF. The product was isolated as a racemic mixture.LCMS calculated for C₂₅H₂₉ClN₇O₃ (M+H)⁺: m/z=510.2; Found: 510.2.

Example 20.2-(4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl)ethanol

Step 1. 3-Bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene

A mixture of cyanuric chloride (1.7 g, 9.2 mmol) andN,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperaturefor 10 minutes and then a solution of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (from Example 16,Step 1) (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added andthe reaction was stirred at room temperature overnight. The mixture wasdiluted with methylene chloride, washed with sat. NaHCO₃, water, brine,dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by silica gel chromatography, eluting with 0 to 10% EtOAc inhexanes (1.01 g, 60%).

Step 2.1-[1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Sodium hydride (36 mg, 0.91 mmol) was added to a mixture of3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (150 mg,0.503 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76mmol) in N,N-dimethylformamide (8 mL) and the reaction was stirred at30° C. overnight. The mixture was diluted with methylene chloride,washed with sat. NaHCO₃, water, brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by silica gelchromatography, eluting with 0 to 70% EtOAc in CH₂Cl₂ (103 mg, 50%).LCMS calculated for C₁₆H₁₈BrClN₅O (M+H)⁺: m/z=410.0; Found: 410. Theracemic products were applied on a Phenomenex Lux-Cellulose 1 column(21.1×250 mm, 5 micron particle size), eluting with 5% ethanol inhexanes at a flow rate of 18 mL/min, ˜13 mg/injection, to provide twoenantiomers.

Step 3.1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Potassium tert-butoxide (1.0 M) in THF (0.60 mL, 0.60 mmol) was added toa solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The reaction mixturewas stirred at room temperature for 5 minutes, then cooled to 0° C. andtreated with (2-bromoethoxy)(tert-butyl)dimethylsilane (0.2 mL, 0.8mmol). The reaction was stirred at room temperature overnight, thendiluted with ethyl acetate, washed with sat. NaHCO₃, water, brine, driedover Na₂SO₄, filtered and concentrated to provide the crude productwhich was purified by silica gel chromatography eluting with 0 to 30%EtOAc in hexanes. Calculated for C₁₇H₃₄BN₂O₃Si (M+H)⁺: m/z=353.2; Found:353.1.

Step 4.2-(4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl)ethanol

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.026 g, 0.062 mmol) (chiral pure, first peak from Step 2),1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.024 g, 0.069 mmol), sodium carbonate (13 mg, 0.12 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (6.1 mg, 0.0075 mmol) in acetonitrile (0.5mL)/water (0.1 mL) was degassed and then refilled with N₂. The reactionmixture was stirred at 95° C. for 2 hours, then treated with conc. HCl(0.1 mL) and then stirred at room temperature for 1 hour. The crudemixture was purified using RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give the desired product. The product wasisolated as a single enantiomer. LCMS calculated for C₂₁H₂₅ClN₇O₂(M+H)⁺: m/z=442.2; Found: 442.2.

Example 21.3′-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-N,N,6′-trimethylbiphenyl-4-carboxamidetrifluoroacetate

Step 1. Methyl3′-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(60 mg, 0.15 mmol, chiral pure, first peak from Example 20, Step 2),[3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (from Combi-Blocks,0.041 g, 0.20 mmol), sodium carbonate (36 mg, 0.34 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (6 mg, 0.007 mmol) in acetonitrile (1.2mL)/water (0.3 mL) was vacuumed and then refilled with N₂. The reactionwas stirred at 95° C. for 2 hours. Then solvent was removed and thecrude mixture was purified by silica gel chromatography, eluting with 0to 70% EtOAc in CH₂Cl₂, to give the desired product (54 mg, 75%). LCMScalculated for C₂₄H₂₄ClFN₅O₃ (M+H)⁺: m/z=484.2; Found: 484.1.

Step 2.3′-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylicacid

Lithium hydroxide, monohydrate (13 mg, 0.31 mmol) was added to asolution of methyl3′-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylatemade above (0.030 g, 0.062 mmol) in methanol (0.2 mL)/tetrahydrofuran(0.2 mL)/water (0.09 mL). The reaction was stirred at room temperaturefor 1.5 h, then treated with conc. HCl (60 uL) to adjust pH to 2. Thesolvent was removed to provide the crude product which was used in nextstep without further purification. LCMS calculated for C₂₃H₂₂ClFN₅O₃(M+H)⁺: m/z=470.1; Found: 470.2.

Step 3.3′-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-N,N,6′-trimethylbiphenyl-4-carboxamidetrifluoroacetate

2.0 M Dimethylamine in THF (0.1 mL, 0.2 mmol) was added to a solution of3′-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylicacid (12 mg, 0.026 mmol) made above andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(20 mg, 0.04 mmol) in N,N-dimethylformamide (0.7 mL) at room temperaturefollowed by addition of triethylamine (11 μL, 0.077 mmol). The reactionwas stirred for 1 hour, quenched with water. The crude mixture wasapplied on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive the desired product as TFA salt. The product was isolated as asingle enantiomer. LCMS calculated for C₂₅H₂₇ClFN₆O₂ (M+H)⁺: m/z=497.2;Found: 497.2.

Example 22.3′-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-N,6′-dimethylbiphenyl-4-carboxamidetrifluoroacetate

This compound was prepared using procedures analogous to those forExample 21, Step 3, with 2.0 M methylamine in THF replacing 2.0 Mdimethylamine in THF. The product was isolated as a single enantiomer.LCMS calculated for C₂₄H₂₅ClFN₆O₂ (M+H)⁺: m/z=483.2; Found: 483.2.

Example 23.5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-(2-hydroxyethyl)picolinamidetrifluoroacetate

Step 1.5-[3-Chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile

A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (0.15g, 0.54 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile(from Frontier, 0.14 g, 0.59 mmol), sodium carbonate (110 mg, 1.1 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (52 mg, 0.064 mmol) in acetonitrile (4mL)/water (1 mL) was degassed and then refilled with N₂. The reactionwas stirred at 95° C. for 2 h, cooled, diluted with ethyl acetate,washed with sat. NaHCO₃, water, brine, and then dried over Na₂SO₄,filtered and concentrated. The crude product was purified by silica gelchromatography, eluting with 0 to 40% EtOAc in hexanes, to give thedesired product (114 mg, 70%). LCMS calculated for C₁₆H₁₆ClN₂O₂ (M+H)⁺:m/z=303.1; Found: 303.0.

Step 2.5-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile

A mixture of cyanuric chloride (170 mg, 0.94 mmol) andN,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperaturefor 10 minutes and then a solution of5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile(190 mg, 0.628 mmol) in methylene chloride (4 mL) was added and thereaction was stirred at room temperature overnight. The mixture wasdiluted with methylene chloride, washed with sat. NaHCO₃, water, brine,dried over Na₂SO₄, then filtered and concentrated. The resultant crudeproduct was used directly in the next step without further purification(110 mg, 55%). LCMS calculated for C₁₆H₁₅Cl₂N₂O (M+H)⁺: m/z=321.0;Found: 321.0.

Step 3.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile

Sodium hydride (20 mg, 0.50 mmol) was added to a mixture of5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile(90 mg, 0.28 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (63 mg,0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirredat 30° C. overnight. The mixture was treated with water and thenfiltered to provide the desired product. LCMS calculated for C₂₂H₂₁ClN₇O(M+H)⁺: m/z=434.1; Found: 434.2.

Step 4.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylicacid

Sodium hydroxide (1.0 M) in water (0.70 mL, 0.70 mmol) was added to amixture of5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile(0.060 g, 0.14 mmol) in ethanol (1.0 mL). The reaction was heated at 95°C. for 6 hours, followed by the addition of conc. HCl to adjust pH to˜3. The solvent was removed and the resultant residue was used in thenext step without further purification. LCMS calculated for C₂₂H₂₂ClN₆O₃(M+H)⁺: m/z=453.1; Found: 453.2.

Step 5.5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-(2-hydroxyethyl)picolinamidetrifluoroacetate

Ethanolamine (15 μL, 0.25 mmol) was added to a solution of5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylicacid (9.6 mg, 0.021 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperaturefollowed by addition of triethylamine (8.8 μL, 0.064 mmol). The reactionwas stirred for 1 hour, and then quenched with water. The crude mixturewas applied on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive the desired product as TFA salt. The product was isolated as aracemic mixture. LCMS calculated for C₂₄H₂₇ClN₇O₃ (M+H)⁺: m/z=496.2;Found: 496.2.

Example 24.4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamidetrifluoroacetate

This compound was prepared using procedures analogous to those forExample 23, with 2-(methylamino)ethanol replacing ethanolamine. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₅H₂₉ClN₇O₃ (M+H)⁺: m/z=510.2; Found: 510.2.

Example 25.5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Step 1.5-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

A mixture of cyanuric chloride (from Aldrich, 690 mg, 3.7 mmol) andN,N-dimethylformamide (290 μL, 3.7 mmol) was stirred at room temperaturefor 10 minutes and then a solution of5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(869 mg, 2.49 mmol) in methylene chloride (14 mL) was added and thereaction was stirred at room temperature overnight. The mixture wasdiluted with methylene chloride, washed with sat. NaHCO₃, water, brine,dried over Na₂SO₄, filtered and concentrated. The product was purifiedby silica gel chromatography, eluting with 0 to 100% EtOAc in hexanes.

Step 2.5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (from VWR, 4.8mg, 0.030 mmol), cesium carbonate (14 mg, 0.044 mmol) and potassiumiodide (0.50 mg, 0.0030 mmol) in N,N-dimethylformamide (0.1 mL) wasadded5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(11 mg, 0.030 mmol). The mixture was stirred at 140° C. for 1 hour. Thereaction mixture was applied on RP-HPLC (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. LCMScalculated for C₂₅H₂₆ClN₆O₃ (M+H)⁺: m/z=493.2; Found: 493.1. The racemicproducts were applied on a Phenomenex Lux-Cellulose 1 column (21.1×250mm, 5 micron particle size), eluting with 30% ethanol in hexanes at aflow rate of 18 mL/min, 4.2 mg/injection, to provide two isolatedenantiomers. This first isolated peak had a retention time of 15.39 minand the second peak had a retention time of 22.98. For the second peak:¹H NMR (CDCl₃, 400 MHz) δ 9.86 (d, J=5.6 Hz, 1H), 8.36 (m, 1H), 8.30 (s,1H), 7.65˜7.58 (m, 2H), 7.37 (m, 2H), 6.84 (q, J=7.2 Hz, 1H), 6.22 (d,J=8.0 Hz), 5.95 (d, J=5.2 Hz, 1H), 3.08 (s, 3H), 3.05 (s, 3H), 2.93 (m,3H), 2.09 (s, 3H), 1.68 (d, J=7.2 Hz, 3H) ppm.

Example 26.4-Amino-8-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)pyrido[2,3-d]pyrimidin-5(8H)-onebis(trifluoroacetate)

Step 1. 3-Bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene

A mixture of cyanuric chloride (1.7 g, 9.2 mmol) andN,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperaturefor 10 minutes and then a solution of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (1.72 g, 6.15 mmol)in methylene chloride (34 mL) was added and the reaction was stirred atroom temperature overnight. The mixture was diluted with methylenechloride, washed with sat. NaHCO₃, water, brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by silica gelchromatography, eluting with 0 to 10% EtOAc in hexanes.

Step 2.4-Amino-8-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.80 g, 4.9mmol), cesium carbonate (2.4 g, 7.3 mmol) and potassium iodide (82 mg,0.49 mmol) in N,N-dimethylformamide (20 mL) was added3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (1.47 g,4.93 mmol) and the mixture was stirred at 140° C. for 1 hour. Themixture was diluted with water and ethyl acetate. The precipitate wascollected and dried to give the desired compound. LCMS calculated forC₁₇H₁₇BrClN₄O₂ (M+H)⁺: m/z=423.0; Found: 423.0.

Step 3.4-Amino-8-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)pyrido[2,3-d]pyrimidin-5(8H)-onebis(trifluoroacetate)

A mixture of4-amino-8-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one(25 mg, 0.059 mmol),3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(from PepTech, 18 mg, 0.065 mmol), sodium carbonate (13 mg, 0.12 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (5.8 mg, 0.0071 mmol) in acetonitrile (0.5mL)/water (0.1 mL) was degassed with N₂ and the then stirred at 90° C.for 2 hour. The crude mixture was cooled and purified by RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) togive the desired product. The product was isolated as a racemic mixture.LCMS calculated for C₂₃H₂₃ClN₅O₄S (M+H)⁺: m/z=500.1; Found: 500.0.

Example 27.5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}nicotinonitrilebis(trifluoroacetate)

This compound was prepared using procedures analogous to those forExample 26, with 3-cyanopyridine-5-boronic acid pinacol ester (fromFrontier) replacing3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as a racemic mixture. LCMS calculated forC₂₃H₂₀ClN₆O₂ (M+H)⁺: m/z=447.1; Found: 447.1.

Example 28.4-Amino-8-[1-(5-chloro-2-methoxy-4-methyl-3-pyridin-3-ylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-onebis(trifluoroacetate)

This compound was prepared using procedures analogous to those forExample 26, with pyridine-3-boronic acid (from Aldrich) replacing3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as a racemic mixture. LCMS calculated forC₂₂H₂₁ClN₅O₂ (M+H)⁺: m/z=422.1; Found: 422.0.

Example 29.4-Amino-8-[1-(5-chloro-2-methoxy-4-methyl-3-pyrimidin-5-ylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-onebis(trifluoroacetate)

This compound was prepared using procedures analogous to those forExample 26, with pyrimidine-5-boronic acid (from Frontier) replacing3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as a racemic mixture. LCMS calculated forC₂₁H₂₀ClN₆O₂ (M+H)⁺: m/z=423.1; Found: 423.0.

Example 30.3′-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5′-chloro-2′-methoxy-N,N,6′-trimethylbiphenyl-3-carboxamidebis(trifluoroacetate)

This compound was prepared using procedures analogous to those forExample 26, with 3-(N,N-dimethylaminocarbonyl)benzene boronic acid (fromFrontier) replacing3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as a racemic mixture. LCMS calculated forC₂₆H₂₇ClN₅O₃ (M+H)⁺: m/z=492.2; Found: 492.1.

Example 31.4-Amino-8-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-onebis(trifluoroacetate)

This compound was prepared using procedures analogous to those forExample 26, with 5-fluoropyridine-3-boronic acid (from Combi-Blocks)replacing3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as a racemic mixture. LCMS calculated forC₂₂H₂₀ClFN₅O₂ (M+H)⁺: m/z=440.1; Found: 440.0.

Example 32.3′-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5′-chloro-2′-methoxy-N,N,6′-trimethylbiphenyl-3-sulfonamidebis(trifluoroacetate)

This compound was prepared using procedures analogous to those forExample 26, with N,N-dimethyl 3-boronobenzenesulfonamide (fromCombi-Blocks) replacing3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as a racemic mixture. LCMS calculated forC₂₅H₂₇ClN₅O₄S (M+H)⁺: m/z=528.1; Found: 528.1.

Example 33.5-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylpyridine-2-carboxamidebis(trifluoroacetate)

This compound was prepared using procedures analogous to those forExample 26, with 2-(N-methylamidocarboxy)-5-pyridine boronic acid pincolester (from Frontier) replacing3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as a racemic mixture. LCMS calculated forC₂₄H₂₄ClN₆O₃ (M+H)⁺: m/z=479.2; Found: 479.1.

Example 34.4-Amino-8-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one

Step 1. tert-Butyl3-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (from VWR) (8.6mg, 0.053 mmol), cesium carbonate (26 mg, 0.080 mmol) and potassiumiodide (0.89 mg, 0.0053 mmol) in N,N-dimethylformamide (0.2 mL) wasadded tert-butyl3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate(20 mg, 0.05 mmol, from Example 1, step 5, racemic intermediate). Themixture was stirred at 140° C. for 1 hour, then cooled and was dilutedwith water, extracted with ether. The organic layers were dried overMgSO₄ and concentrated to afford the crude product which was used in thenext step directly. LCMS calculated for C₂₅H₃₁ClN₅O₄ (M+H)⁺: m/z=500.2;Found: 500.1.

Step 2.4-Amino-8-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one

A solution of tert-butyl3-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate(27 mg, 0.053 mmol) in methylene chloride (0.25 mL) was treated with 4.0M hydrogen chloride in dioxane (0.13 mL, 0.50 mmol) at room temperaturefor 1 hour, then stripped to dryness to give4-amino-8-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-oneas HCl salt.

To a mixture of the crude HCl salt in acetonitrile (0.2 mL)/methanol(0.2 mL)/tetrahydrofuran (0.2 mL) was added N,N-diisopropylethylamine(0.046 mL, 0.27 mmol). The mixture was stirred at room temperature untilthe solid dissolved, then treated with acetone (0.032 mL, 0.43 mmol).The resulting mixture was stirred for 30 minutes before the addition ofsodium triacetoxyborohydride (0.034 g, 0.16 mmol). The reaction mixturewas stirred at room temperature for 4 hours, then quenched and appliedon RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product. The product was isolated as aracemic mixture. LCMS calculated for C₂₃H₂₉ClN₅O₂ (M+H)⁺: m/z=442.2;Found: 442.1.

Example 35.4-Amino-8-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-onebis(trifluoroacetate)

Step 1. Benzyl3-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate

Zinc (0.967 g, 14.8 mmol) was suspended with 1,2-dibromoethane (0.085mL, 0.98 mmol) in N,N-dimethylformamide (17 mL). The mixture was heatedat 70° C. for 10 minutes and then cooled to room temperature.Chlorotrimethylsilane (0.125 mL, 0.984 mmol) was added dropwise andstirring was continued for 1 hour. A solution of benzyl3-iodoazetidine-1-carboxylate (from PharmaBlock) (3.9 g, 12 mmol) inN,N-dimethylformamide (10 mL) was then added and the mixture was heatedat 40° C. for 1 hour before a mixture of1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (4.4 g, 13 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.22 g, 0.24 mmol) andtri-(2-furyl)phosphine (0.12 g, 0.50 mmol) in N,N-dimethylformamide (30mL) was added. The reaction mixture was warmed to 70° C. and stirredovernight. The mixture was then cooled to room temperature andpartitioned between ether and sat. NH₄Cl solutions. The organic layerswere washed with water, dried over MgSO₄, concentrated and purified onsilica gel (eluting with 0 to 20% EtOAc in hexanes) to give the desiredproduct (3.87 g, 78%). LCMS calculated for C₂₂H₂₅ClNO₄ (M+H)⁺:m/z=402.1; Found: 402.1.

Step 2. Benzyl3-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]azetidine-1-carboxylate

To a solution of benzyl3-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate(0.35 g, 0.87 mmol) in methanol (5 mL) cooled at 0° C. was added sodiumtetrahydroborate (0.040 g, 1.0 mmol). The mixture was stirred at roomtemperature for 1 hour, then diluted with water, extracted with EtOAc.The organic layers were dried over MgSO₄ and concentrated to give thecrude alcohol (0.31 g, 88%). LCMS calculated for C₂₂H₂₇ClNO₄ (M+H)⁺:m/z=404.2; Found: 404.0.

Step 3. Benzyl3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]azetidine-1-carboxylate

Cyanuric chloride (200 mg, 1.1 mmol) was added to N,N-dimethylformamide(0.083 mL, 1.1 mmol) at room temperature. After the formation of a whitesolid (ca. 10 minutes), methylene chloride (5 mL) was added, followed bybenzyl3-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]azetidine-1-carboxylate(310 mg, 0.77 mmol). After addition, the resultant mixture was stirredat room temperature overnight. Water was added, and then diluted withdichloromethane. The organic phases were washed with sat. NaHCO₃solution, water and brine, dried over MgSO₄, concentrated and purifiedon silica gel (eluting with 0 to 40% EtOAc/hexanes) to give the desiredproduct (140 mg, 43%). LCMS calculated for C₂₂H₂₆Cl₂NO₃ (M+H)⁺:m/z=422.1; Found: 422.0.

Step 4. Benzyl3-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (11.5 mg, 0.0708mmol), cesium carbonate (34 mg, 0.10 mmol) and potassium iodide (1.2 mg,0.0071 mmol) in N,N-dimethylformamide (0.2 mL) was added benzyl3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]azetidine-1-carboxylate(30 mg, 0.07 mmol). The mixture was stirred at 140° C. for 1 hour,cooled and then diluted with water, extracted with ether. The combinedorganic layers were dried over MgSO₄ and concentrated to afford thecrude product which was used in the next step directly. LCMS calculatedfor C₂₉H₃₁ClN₅O₄ (M+H)⁺: m/z=548.2; Found: 548.2.

Step 5.4-Amino-8-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-onebis(trifluoroacetate)

To a mixture of benzyl3-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate(23 mg, 0.042 mmol) and 5% palladium on carbon (10 mg) in methanol (1.6mL) was added 0.25 M hydrogen chloride in water (0.42 mL, 0.10 mmol).The suspension was hydrogenated under balloon pressure of H₂ at roomtemperature for 2 hours. After filtered off the catalyst, the filtratewas neutralized with sat. NaHCO₃ solution, extracted withdichloromethane. The combined organic layers were dried over MgSO₄ andconcentrated to give4-amino-8-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one(7 mg, 40%). To a mixture of the crude amine in acetonitrile (0.1mL)/methanol (0.1 mL)/tetrahydrofuran (0.1 mL) was addedN,N-diisopropylethylamine (0.02 mL, 0.1 mmol), followed by acetone (0.03mL, 0.4 mmol). The mixture was stirred for 30 minutes before theaddition of sodium triacetoxyborohydride (0.044 g, 0.21 mmol). Thereaction was stirred at room temperature for 4 hours, then quenched withwater and purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30mL/min) to give the desired product as TFA salt. The product wasisolated as a racemic mixture. LCMS calculated for C₂₄H₃₁ClN₅O₂ (M+H)⁺:m/z=456.2; Found: 456.1.

Example 36.5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (47 mg, 0.29mmol), cesium carbonate (130 mg, 0.39 mmol) and potassium iodide (4.4mg, 0.026 mmol) in N,N-dimethylformamide (0.8 mL) was added5-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(100 mg, 0.3 mmol, from Example 14, step 4, racemic intermediate) andthe mixture was stirred at 140° C. for 1 hour. The resultant mixture wasdiluted with MeOH, filtered and the filtrate was purified on RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 30 mL/min) to give the desiredproduct as TFA salt. The product was isolated as a racemic mixture. LCMScalculated for C₂₆H₂₈ClN₆O₃ (M+H)⁺: m/z=507.2; Found: 507.1.

Example 37.6-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-chloro-N-ethyl-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide

Step 1. 3-Acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile

A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (4.85g, 18.4 mmol) and copper cyanide (2.47 g, 27.6 mmol) inN-methylpyrrolidinone (15 mL) was heated at 200° C. for 1 h. Aftercooled to rt, the mixture was diluted with EtOAc and 1 N HCl. The layerswere separated and the aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with water, then brine and driedover magnesium sulfate, then concentrated to dry under reduced pressure.The residue was used directly in next step (3.7 g, 96%). LCMS calculatedfor C₁₀H₉ClNO₂ (M+H)⁺: m/z=210.0; Found: 210.1.

Step 2. 6-Acetyl-4-chloro-2-cyano-3-methylphenyltrifluoromethanesulfonate

To a mixture of 3-acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile (3.70g, 17.6 mmol) in methylene chloride (70 mL) was added triethylamine (7.4mL, 53 mmol) followed by trifluoromethanesulfonic anhydride (4.4 mL, 26mmol) at −78° C. The reaction was allowed to warm up to rt gradually andstirred at rt for 30 min. After quenched with water, the mixture wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried over sodium sulfate, and concentrated to dry. Theresidue was purified on silica gel, eluting with 0 to 40% EtOAc inhexanes, to give the desired product (2.54 g, 42%). LCMS calculated forC₁₁H₈ClF₃NO₄S (M+H)⁺: m/z=342.0; Found: 342.1.

Step 3. 6-Acetyl-4-chloro-3,5′-difluoro-3-methylbiphenyl-2-carbonitrile

A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyltrifluoromethanesulfonate (3.07 g, 8.98 mmol) and(3,5-difluorophenyl)boronic acid (1.70 g, 10.8 mmol) in toluene (30mL)/0.8 M sodium hydrogencarbonate in water (30 mL, 30 mmol) (this wassaturated NaHCO₃ in water) was degassed with N₂.Tetrakis(triphenylphosphine)palladium(0) (0.414 g, 0.359 mmol) wasadded. The mixture was degassed with N₂ for 5 min. and heated at 80° C.for 2 h. After cool to rt, the mixture was diluted with EtOAc. Thelayers were separated and the aq. layer was extracted with more EtOAc.The combined extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated to crude, dark solid. The material wasdissolved in CHCl₃ and purified on silica gel column, eluting with 0 to20% of EtOAc in hexanes, to give the desired product (2.71 g, 99%). LCMScalculated for C₁₆H₁₁ClF₂NO (M+H)⁺: m/z=306.0; Found: 306.1.

Step 4.4-Chloro-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carbaldehyde

To a mixture of6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile (2.43g, 7.95 mmol) in methylene chloride (50 mL) was added 1.0 Mdiisobutylaluminum hydride in hexane (19.9 mL, 19.9 mmol) at −78° C. Thereaction was warmed to rt over 2 h with stirring. 5.0 M Hydrogenchloride in water (70 mL) was added slowly, and stirring was continuedfor 1 h. The resultant mixture was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over sodium sulfate andthen concentrated to dry. The residue was purified on silica gel,eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.4g, 97%). LCMS calculated for C₁₆H₁₂ClF₂O (M-OH)⁺: m/z=293.1; Found:293.1.

Step 5.4-Chloro-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxylicacid

To a solution of4-chloro-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carbaldehyde(1.00 g, 3.22 mmol) in methanol (40 mL) was added 1.0 M sodium hydroxidein water (16 mL, 16 mmol), followed by 1.0 M sodium hydroxide in water.After stirred at rt overnight, the mixture was slowly acidified to pH 5with 1 N HCl, then extracted with EtOAc. The combined organic layerswere washed with brine, dried over magnesium sulfate, and concentratedto dry under reduced pressure. The crude residue was used directly innext step (1.05 g, 100%).

Step 6.4-Chloro-N-ethyl-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxamide

A mixture of4-chloro-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxylicacid (250 mg, 0.76 mmol), ethylamine hydrochloride (94 mg, 1.1 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.51 g, 1.1 mmol) in N,N-dimethylformamide (4 mL) was stirred at rt for10 min. To the resulting mixture was added N,N-diisopropylethylamine(0.40 mL, 2.3 mmol). After stirred at rt overnight, the reaction wasquenched with water, extracted with EtOAc. The combined organic layerswere washed with water, brine, dried over magnesium sulfate, and thenconcentrated to dry. The residue was purified on silica gel, elutingwith 0 to 80% EtOAc in hexanes, to give the desired product (185 mg,68%). LCMS calculated for C₁₈H₁₉ClF₂NO₂ (M+H)⁺: m/z=354.1; Found: 354.0.

Step 7.1-{4-Chloro-6-[(ethylamino)carbonyl]-3′,5′-difluoro-5-methylbiphenyl-2-yl}ethylmethanesulfonate

To a mixture of4-chloro-N-ethyl-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxamide(185 mg, 0.523 mmol) in methylene chloride (3 mL) was addedN,N-diisopropylethylamine (0.18 mL, 1.0 mmol), followed bymethanesulfonyl chloride (0.061 mL, 0.78 mmol). The reaction was stirredat rt for 10 min, quenched by pouring onto iced water, and extractedwith dichloromethane. The combined organic layers were washed with aq.sodium bicarbonate, dried over magnesium sulfate, and evaporated to dry.The residue was used directly in next step (0.226 g, 100%). LCMScalculated for C₁₉H₂₁ClF₂NO₄S (M+H)⁺: m/z=432.1; Found: 432.1.

Step 8.6-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-chloro-N-ethyl-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide

To a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (fromChemBridge) (26 mg, 0.17 mmol) in N,N-dimethylformamide (0.5 mL) wasadded sodium hydride (14 mg, 0.35 mmol). After stirring at roomtemperature for 30 minutes, to the resulting mixture was added to amixture of1-{4-chloro-6-[(ethylamino)carbonyl]-3′,5′-difluoro-5-methylbiphenyl-2-yl}ethylmethanesulfonate (50 mg, 0.1 mmol) in N,N-dimethylformamide (0.5 mL).The reaction was stirred at room temperature overnight and then quenchedwith water. The resultant mixture was purified on RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give the desiredproduct. The product was isolated as a racemic mixture. LCMS calculatedfor C₂₄H₂₄ClF₂N₆O (M+H)⁺: m/z=485.2; Found: 485.1.

Example 38.4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Step 1.4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile

Sodium hydride (20. mg, 0.50 mmol) was added to a mixture of4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile(from Example 16, Step 3) (90 mg, 0.28 mmol),4-aminopyrazolo[3,4-d]pyrimidine (from Acros Organics) (57 mg, 0.42mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirred at30° C. overnight. The mixture was treated with water and then filteredto provide the desired product. LCMS calculated for C₂₁H₁₉ClN₇O (M+H)⁺:m/z=420.1; Found: 420.1.

Step 2.4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylicacid

1.0 M Sodium hydroxide in water (0.3 mL, 0.3 mmol) was added to amixture of4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile(60 mg, 0.14 mmol) in ethanol (0.3 mL). The reaction mixture was heatedat 95° C. for 6 h, then treated with conc. HCl to adjust the pH to ˜3.The solvent was removed under reduced pressure and the resulting residuewas used in the next step without further purification. calculated forC₂₁H₂₀ClN₆O₃ (M+H)⁺: m/z=439.1; Found: 439.2.

Step 3.4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Dimethylamine (2.0 M) in THF (0.14 mL, 0.28 mmol) was added to asolution of4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylicacid (18.6 mg, 0.042 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperaturefollowed by the addition of triethylamine (8.8 μL, 0.064 mmol). Thereaction was stirred for 1 hour, then quenched with water. The mixturewas purified on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product. The product was isolated as aracemic mixture. LCMS calculated for C₂₃H₂₅ClN₇O₂ (M+H)⁺: m/z=466.2;Found: 466.2.

Example 39.4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)pyridine-2-carboxamide

Ethanolamine (2.0 M) in THF (0.14 mL, 0.28 mmol) was added to a solutionof4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylicacid (from Example 38, Step 2) (18.6 mg, 0.042 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperaturefollowed by adding triethylamine (8.8 μL, 0.064 mmol). The reaction wasstirred for 1 hour, then quenched with water. The mixture was purifiedon RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product. The product was isolated as aracemic mixture. LCMS calculated for C₂₃H₂₅ClN₇O₃ (M+H)⁺: m/z=482.2;Found: 482.2.

Example 40.4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-cyano-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide

Catalyst preformation: Anhydrous dimethylacetamide (DMA) was purged witha gentle stream of N₂ for 30 minutes prior to use. A 50 mM solution ofH₂SO₄ was prepared with 10 mL dimethylacetamide and 26.8 μL of conc.H₂SO₄ and then purged with N₂ for 10 minutes. To an 8 mL vial equippedwith a magnetic stir bar and septum cap were added Pd(OAc)₂ (22.5 mg,100 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(95.3 mg, 200 μmol). The vial was evacuated and filled with N₂ threetimes, purged with a gentle stream of N₂ for 10 minutes. H₂SO₄ (2.0 mL,50 mM in DMA) was added, and the catalyst mixture was stirred in an oilbath at 80° C. for 30 minutes to give a homogeneous coffee-brownsolution.

The above catalyst (0.05 mL) was added to a mixture of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide(from Example 19) (4.0 mg, 0.0078 mmol), zinc (0.22 mg, 0.0034 mmol) andzinc cyanide (0.92 mg, 0.0078 mmol) in N,N-dimethylacetamide (0.1 mL).The mixture was degassed and then the reaction was heated at 120° C. for1.5 hours. The crude mixture was applied on RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₆H₂₉N₈O₃ (M+H)⁺: m/z=501.2; Found: 501.2.

Example 41.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

Step 1:N-(2,4-Dimethoxybenzyl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine

A solution of 4-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (330 mg, 1.9mmol) and 1-(2,4-dimethoxyphenyl)methanamine (0.58 mL, 3.9 mmol) in1-butanol was heated in the microwave at 150° C. for 40 minutes.Purification via preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) gave the desired product (240 mg, 42%). LCMS forC₁₆H₁₉N₄O₂ (M+H)⁺: m/z=299.1; Found: 299.2.

Step 2:5-[3-Chloro-5-(1-{4-[(2,4-dimethoxybenzyl)amino]-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl}ethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

A solution ofN-(2,4-dimethoxybenzyl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (110mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was treated with sodiumhydride (30 mg, 0.75 mmol) and stirred at 20° C. for 30 minutes. Thereaction mixture was treated with a solution of5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(130 mg, 0.34 mmol) in N,N-dimethylformamide (1 mL) and heated at 50° C.overnight. The reaction mixture was diluted with water and extractedwith ethyl acetate (2×). The combined organic extracts were washed withwater and brine, dried with magnesium sulfate, filtered, andconcentrated to a crude residue. Purification via preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave thedesired product (110 mg, 49%). LCMS for C₃₄H₃₈ClN₆O₄ (M+H)⁺: m/z=629.3;Found: 629.1.

Step 3:5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

A solution of5-[3-chloro-5-(1-{4-[(2,4-dimethoxybenzyl)amino]-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl}ethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(85 mg, 0.14 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (2 mL) and stirred at 20° C. for 3 hours and at 40°C. for 20 minutes. Purification via preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%trifluoroacetic acid, at flow rate of 60 mL/min) gave the desiredproduct (44 mg, 46%). The product was isolated as a racemic mixture.LCMS for C₂₅H₂₈ClN₆O₂ (M+H)⁺: m/z=479.2; Found: 479.0. ¹H NMR (300 MHz,DMSO-d₆): δ 12.8 (br s, 0.5H), 8.50 (br s, 0.5H), 8.37 (br s, 2H),7.91-7.86 (m, 0.5H), 7.80-7.75 (m, 0.5H), 7.68-7.58 (m, 3H), 7.17 (d,J=7.3 Hz, 1H), 6.19 (q, J=6.9 Hz, 1H), 3.04 (s, 3H), 3.01 (s, 3H), 2.94(s, 3H), 2.61 (s, 3H), 2.05 (s, 3H), 1.83 (d, J=6.9 Hz, 3H).

Example 42.5-{3-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

The desired compound was prepared according to the procedure of Example41, step 2, using 5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ACESPharma, 57974] as the starting material in 18% yield. The product wasisolated as a racemic mixture. LCMS for C₂₅H₂₈ClN₆O₂ (M+H)⁺: m/z=479.2;Found: 479.3. ¹H NMR (300 MHz, DMSO-d₆): δ 8.46 (br s, 1H), 8.31 (br s,1H), 8.28 (s, 1H), 7.87-7.83 (m, 1H), 7.65-7.61 (m, 1H), 7.51 (s, 1H),7.48 (s, 1H), 6.24 (q, J=7.0 Hz, 1H), 3.08 (s, 3H), 3.01 (s, 3H), 2.95(s, 3H), 2.40 (s, 3H), 2.05 (s, 3H), 1.78 (d, J=7.2 Hz, 3H).

Example 43.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile

Step 1. 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone

1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone (e.g., from Example 13,step 1) (20.0 g, 101 mmol, 1.00 eq) and a 50% aqueous sulfuric acid (120mL) were added to the flask. The resulting mixture was heated to 60° C.in a water bath with stirring. N-Bromosuccinimide (21.52 g, 120.9 mmol,1.20 eq) was added in three portions [7.0 g+7.0 g+7.52 g] in 8 minuteintervals. After the reaction mixture was heated at 60° C. for 3 hours,the reaction was complete. The reaction mixture was diluted with water(160 ml) and dichloromethane (DCM) (300 ml), and the mixture was stirredfor 0.5 hour. The organic layer was separated and the aqueous layer wasextracted with dichloromethane (100 ml). The combined organic layerswere washed with 1 N HCl (100 ml×2), water (100 ml), brine (60 ml), andconcentrated under reduced pressure to afford the crude product (29.1 g)as a yellowish solid. The crude product was dissolved in HOAc (100 ml)and then diluted with water (200 ml) under stirring. The resultingmixture was stirred for 20 min at room temperature and the product wascollected by filtration and dried to give1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (21.8 g, 80.9%) asa yellowish solid. ¹H-NMR (300 MHz, CDCl₃) δ 13.18 (s, 1H, —OH), 7.78(d, J=7.78 Hz, 1H), 2.63 (s, 3H).

Step 2. 4-Acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile

1-(3-Bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (2.0 g, 7.5 mmol)was combined with potassium cyanide (0.58 g, 9.0 mmol) inN,N-dimethylformamide (16 mL, 210 mmol) and heated to 85° C. in an oilbath. After heating for 18 hours, the reaction was allowed to cool toroom temperature and iodoethane (0.90 mL, 11 mmol) and potassiumcarbonate (2.1 g, 15 mmol) were added. The reaction was heated to 65° C.and monitored by LC/MS. After heating for 3 hours the reaction wascomplete and allowed to cool to room temperature, then taken up in ethylacetate and washed with water, brine, and dried over magnesium sulfate.The resultant solution was concentrated to give the crude product as adark oil. The product was purified by flash column chromatography onsilica gel eluting hexane: ethyl acetate gradient to give4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile (1.15 gm, 50%) as a solidresidue, LCMS calculated for C₁₁H₉BrClNO₂ (M+H)⁺: m/z=301.9, 303.9;found: (no ionization)

Step 3. 2-Bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile

Sodium tetrahydroborate (38 mg, 0.99 mmol) was added to a mixture of4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile (200 mg, 0.7 mmol) inmethanol (5 mL, 100 mmol) at 0° C. The reaction was stirred at roomtemperature for 1 hour, concentrated and partitioned between water andEtOAc. The combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated to give crude2-bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile as a clear oil(0.15 gm, 100%), LCMS calculated for C₁₁H₁₁BrClNO₂ (M+H)⁺: m/z=303.9,305.9; found: 304.0, 305.9.

Step 4. 2-Bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile

Cyanuric chloride (0.11 g, 0.59 mmol) was dissolved inN,N-dimethylformamide (3 mL, 40 mmol). After stirring for a few minutes,a solution of 2-bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile(150 mg, 0.49 mmol) in methylene chloride (3 mL, 50 mmol) was added. Theresulting mixture was stirred at room temperature overnight. Thereaction was partitioned between water and dichloromethane. The organiclayer was washed with sat. NaHCO₃ solution, water, brine, dried overMgSO₄, and concentrated. The crude product was purified by flash columnchromatography, eluting a gradient of 0-30% EtOAc/Hexane to give2-bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (0.12 gm, 75%)as a semisolid, LCMS calculated for C₁₁H₁₀BrCl₂NO (M+H)⁺: m/z=323.9,320.9; found: (poor ionization).

Step 5.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile

Sodium hydride (16 mg, 0.41 mmol) was added to a mixture of3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (33 mg, 0.22 mmol) inN,N-dimethylformamide (3 mL, 40 mmol) and was stirred for 10 minutes.2-bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (60 mg, 0.2mmol) in N,N-dimethylformamide (2 mL) was added and the reaction wasstirred at 50° C. overnight. The mixture was diluted with methylenechloride, washed with sat'd NaHCO₃, water, brine, dried over Na₂SO₄,filtered and concentrated. The product was purified by flash columnchromatography eluting with CH₂Cl₂/MeOH 0-10%, to give4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile(0.05 gm, 60%) as a solid, LCMS calculated for C₁₇H₁₆BrClN₆O (M+H)⁺:m/z=437.0, 435.0; found: 436.9, 434.7.

Step 6.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile

To a mixture of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile(20 mg, 0.04 mmol) and3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(19 mg, 0.069 mmol) in acetonitrile (2 mL, 40 mmol) was added sodiumcarbonate (10 mg, 0.09 mmol) in water (0.5 mL, 30 mmol). The reactionwas degassed with bubbling nitrogen.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (2 mg, 0.002 mmol) was added and degassed morewith N₂. Reaction was heated at 100° C. for 2 hours. The crude productwas purified on preparative LC-MS (acetonitrile, water, TFA) to give thedesired product (0.004 g, 20%) as white amorphous solid. The product wasisolated as a racemic mixture. LCMS calculated for C₂₃H₂₂ClN₇O₃S (M+H)⁺:m/z=512.1; found: 512.2. ¹H NMR (500 MHz, DMSO) δ 9.20 (d, J=2.1 Hz,1H), 9.12 (d, J=1.9 Hz, 1H), 8.61 (t, J=2.0 Hz, 1H), 8.12 (s, 1H), 7.80(s, 1H), 6.36 (q, J=7.0 Hz, 1H), 3.54 (dt, J=14.0, 7.0 Hz, 1H), 3.37 (s,3H), 3.36-3.30 (m, 1H), 2.58 (s, 3H), 1.81 (d, J=7.0 Hz, 3H), 0.92 (t,J=6.9 Hz, 3H).

Example 44.5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-6-cyano-2-ethoxyphenyl)-N,N-dimethylpicolinamide

The title compound was prepared in analogous manor as Example 43, step 6but usingN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(Peptech, Cat #BE1622) to give the crude product which was purified onpreparative LC-MS (acetonitrile, water, TFA) to give the desired product(0.005 g, 22%) as white amorphous solid. The product was isolated as aracemic mixture. LCMS calculated for C₂₅H₂₅ClN₈O₂ (M+H)⁺: m/z=505.1;found: 505.1. ¹H NMR (500 MHz, DMSO) δ 8.72 (dd, J=2.1, 0.7 Hz, 1H),8.14-8.12 (m, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.71 (dd, J=8.0, 0.7 Hz,1H), 6.35 (q, J=7.0 Hz, 1H), 3.61-3.48 (m, 1H), 3.42-3.31 (m, 1H), 3.03(s, 3H), 2.95 (s, 3H), 2.57 (s, 3H), 1.80 (d, J=7.1 Hz, 3H), 0.92 (t,J=7.0 Hz, 3H).

Example 45.5-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide

Step 1.4-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile

Sodium hydride (16 mg, 0.41 mmol) was added to a mixture of4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (36 mg, 0.22 mmol) inN,N-dimethylformamide (3 mL, 40 mmol) and was stirred for 10 minutes.2-Bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (Example 43,step 4) (60 mg, 0.2 mmol in N,N-dimethylformamide (2 mL) was added andthe reaction was stirred at 50° C. overnight. The mixture was dilutedwith methylene chloride, washed with sat'd NaHCO₃, water, brine, driedover Na₂SO₄, filtered and concentrated. The product was purified by FCCeluting with CH₂Cl₂/MeOH (0-10%), to give4-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile(0.04 g, 50%) as a solid, LCMS calculated for C₁₈H₁₅BrClN₅O₂ (M+H)⁺:m/z=450.0, 448.0; found: 450.0, 448.0.

Step 2.5-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide

To a mixture of4-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile(20 mg, 0.04 mmol) and {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronicacid (13 mg, 0.069 mmol) in acetonitrile (2 mL, 40 mmol) was addedsodium carbonate (10 mg, 0.09 mmol) in water (0.5 mL, 30 mmol). Thereaction was degassed with bubbling nitrogen.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (2 mg, 0.002 mmol) was added and degassed morewith N2. Reaction was heated at 100° C. for 1 h. The crude product waspurified on preparative LC-MS (acetonitrile, water, TFA) to give thedesired product (0.005 g, 20%) as white amorphous solid. The product wasisolated as a racemic mixture. LCMS calculated for C₂₆H₂₄ClN₇O₃ (M+H)⁺:m/z=518.1; found: 518.1.

Example 46.4-(1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl)-6-chloro-3-ethoxy-2-(5-(methylsulfonyl)pyridin-3-yl)benzonitrile

The title compound was prepared in an analogous manor as Example 45,Step 2, but using3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(from Anisyn Inc., Cat #CT601515-3) to give the crude product which waspurified on preparative LC-MS (acetonitrile, water, TFA) to give thedesired product (0.005 g, 22%) as white amorphous solid. The product wasisolated as a racemic mixture. LCMS calculated for C₂₄H₂₁ClN₆O₂S (M+H)⁺:m/z=525.1; found: 525.2.

Example 47.5-(3-{1-[4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

To a solution of5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(from Example 15) (15 mg, 0.025 mmol), (3-fluorophenyl)boronic acid(from Aldrich) (6.9 mg, 0.050 mmol), sodium carbonate (16 mg, 0.15 mmol)in N,N-dimethylformamide (0.1 mL)/water (74 μL) under N₂ was addedtetrakis(triphenylphosphine)palladium (0) (2.9 mg, 0.0025 mmol). Themixture was heated at 100° C. overnight. After cooling to roomtemperature, the mixture was filtered and the filtrate purified onRP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% trifluoroacetic acid, at flow rateof 30 mL/min) to give the desired product as bis-TFA salt. The productwas isolated as a racemic mixture. LCMS calculated for C₃₀H₃₀ClFN₇O₂(M+H)⁺: m/z=574.2; Found: 574.2.

Example 48.5-(3-{1-[4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (fromAldrich) instead of (3-fluorophenyl)boronic acid. The product wasisolated as a racemic mixture. LCMS calculated for C₂₇H₂₉ClN₉O₂ (M+H)⁺:m/z=546.2; Found: 546.2.

Example 49.5-(3-{1-[4-amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(from Aldrich) instead of (3-fluorophenyl)boronic acid. The product wasisolated as a racemic mixture. LCMS calculated for C₂₈H₃₁ClN₉O₂ (M+H)⁺:m/z=560.2; Found: 560.2.

Example 50.5-(3-{1-[4-amino-3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(from Frontier) instead of (3-fluorophenyl)boronic acid. The product wasisolated as a racemic mixture. LCMS calculated for C₂₈H₃₁ClN₉O₂ (M+H)⁺:m/z=560.2; Found: 560.2.

Example 51.5-(3-{1-[4-amino-3-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(from Aldrich) instead of (3-fluorophenyl)boronic acid. The crudemixture was treated with conc. HCl (0.1 mL) at room temperature for 1hour before purification. The product was isolated as a racemic mixture.LCMS calculated for C₂₇H₂₉ClN₉O₂ (M+H)⁺: m/z=546.2; Found: 546.2.

Example 52.5-[3-(1-{4-amino-3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(from Example 20, Step 3) instead of (3-fluorophenyl)boronic acid. Thecrude mixture was treated with conc. HCl (0.1 mL) at rt for 1 hourbefore purification. The product was isolated as a racemic mixture. LCMScalculated for C₂₉H₃₃ClN₉O₃ (M+H)⁺: m/z=590.2; Found: 590.2.

Example 53.5-{3-[1-(4-amino-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

A mixture of5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(11 mg, 0.018 mmol, racemic intermediate from Example 15), potassiumcyclopropyltrifluoroborate (3.2 mg, 0.022 mmol), potassium phosphate (12mg, 0.054 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.42 mg,0.00036 mmol) in toluene (0.05 mL)/water (0.02 mL) (v/v, 3/1) was heatedat reflux overnight. The mixture was diluted with MeOH, and thenfiltered. The filtrate was purified on RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.05%trifluoroacetic acid, at flow rate of 30 mL/min) to give the desiredproduct as bis-TFA salt. The product was isolated as a racemic mixture.LCMS calculated for C₂₇H₃₁ClN₇O₂ (M+H)⁺: m/z=520.2; Found: 520.2.

Example 54.5-{3-[1-(4-amino-3-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

A mixture of5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(13 mg, 0.021 mmol, racemic intermediate from Example 15) and coppercyanide (12 mg, 0.13 mmol) in N,N-dimethylformamide (0.2 mL) was heatedat 120° C. overnight. The mixture was filtered and purified on RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to givethe desired product. The product was isolated as a racemic mixture. LCMScalculated for C₂₅H₂₆ClN₅O₂ (M+H)⁺: m/z=505.2; Found: 505.2.

Example 55.5-(3-{1-[4-amino-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using 4-fluorophenylboronic acid (from Aldrich) instead of(3-fluorophenyl)boronic acid. The product was isolated as a racemicmixture. LCMS calculated for C₃₀H₃₀ClFN₇O₂ (M+H)⁺: m/z=574.2; Found:574.2.

Example 56.5-{4-amino-1-[1-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, usingN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(from PepTech) instead of (3-fluorophenyl)boronic acid. The product wasisolated as a racemic mixture. LCMS calculated for C₃₂H₃₅ClN₉O₃ (M+H)⁺:m/z=628.3; Found: 628.3.

Example 57.5-(3-{1-[4-amino-3-(5-cyanopyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (fromFrontier) instead of (3-fluorophenyl)boronic acid. The product wasisolated as a racemic mixture. LCMS calculated for C₃₀H₂₉ClN₉O₂ (M+H)⁺:m/z=582.2; Found: 582.2.

Example 58.5-(3-{1-[4-amino-3-(2-aminopyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine insteadof (3-fluorophenyl)boronic acid. The product was isolated as a racemicmixture. LCMS calculated for C₂₈H₃₀ClN₁₀O₂ (M+H)⁺: m/z=573.2; Found:573.2.

Example 59.5-{3-[1-(4-amino-3-{6-[(methylamino)carbonyl]pyridin-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, usingN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(from Frontier) instead of (3-fluorophenyl)boronic acid. The product wasisolated as a racemic mixture. LCMS calculated for C₃₁H₃₃ClN₉O₃ (M+H)⁺:m/z=614.2; Found: 614.2.

Example 60.5-{3-[1-(4-amino-3-pyridin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using 4-pyridinylboronic acid (from Aldrich) instead of(3-fluorophenyl)boronic acid. The product was isolated as a racemicmixture. LCMS calculated for C₂₉H₃₀ClN₈O₂ (M+H)⁺: m/z=557.2; Found:557.2.

Example 61.5-{3-[1-(4-amino-3-pyridin-3-yl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, using 3-pyridinylboronic acid (from Aldrich) instead of(3-fluorophenyl)boronic acid. The product was isolated as a racemicmixture. LCMS calculated for C₂₉H₃₀ClN₈O₂ (M+H)⁺: m/z=557.2; Found:557.2.

Example 62.5-{3-[1-(4-amino-3-{5-[(dimethylamino)carbonyl]pyridin-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

This compound was prepared according to the procedure described inExample 47, usingN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide(from PepTech) instead of (3-fluorophenyl)boronic acid. The product wasisolated as a racemic mixture. LCMS calculated for C₃₂H₃₅ClN₉O₃ (M+H)⁺:m/z=628.3; Found: 628.3.

Example 63.1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-oxetan-3-ylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (21 mg, 0.046 mmol, racemic intermediate from Example 2,Step 1), oxetan-3-one (from Synthonix, 3.6 mg, 0.050 mmol), andtriethylamine (20 μL, 0.14 mmol) in methylene chloride (0.32 mL) wasadded resin of sodium triacetoxyborohydride (40 mg, 0.091 mmol). Theresulting mixture was stirred overnight at room temperature. The mixturewas filtered and concentrated and then purified by RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give the desiredproduct (2 mg, 9.9%). The product was isolated as a racemic mixture.LCMS calculated for C₂₂H₂₈ClN₆O₂ (M+H)⁺: m/z=443.2; Found: 443.1.

Example 64.1-(1-{5-chloro-2-methoxy-4-methyl-3-[1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (21 mg, 0.046 mmol, racemic intermediate from Example 2,Step 1)), tetrahydro-4H-pyran-4-one (from Aldrich, 4.6 μL, 0.050 mmol),and triethylamine (20 μL, 0.14 mmol) in methylene chloride (0.32 mL) wasadded resin of sodium triacetoxyborohydride (40 mg, 0.091 mmol). Theresulting mixture was stirred overnight at rt. The mixture was filteredand concentrated and then purified by RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₄H₃₂ClN₆O₂ (M+H)⁺: m/z=471.2; Found: 471.2.

Example 65.5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylnicotinamide

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(25 mg, 0.061 mmol) (chiral pure, first peak from Example 20, Step 2),N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide(from PepTech) (25 mg, 0.091 mmol), sodium carbonate (13 mg, 0.12 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II),complex with dichloromethane (1:1) (9.9 mg, 0.012 mmol) in acetonitrile(0.8 mL)/water (0.3 mL) was degassed with N₂ and then stirred at 95° C.for 2 h. The mixture was filtered and the filtrate purified by RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to givethe desired product. The product was isolated as a single enantiomer.LCMS calculated for C₂₄H₂₇ClN₇O₂ (M+H)⁺: m/z=480.2; Found: 480.2. ¹H NMR(500 MHz, DMSO-d₆) δ 8.64 (1H, s), 8.54 (1H, br s), 8.13 (1H, s), 7.82(1H, m), 7.53 (1H, s), 7.42 (2H, br s), 6.28 (1H, q, J=6.5 Hz), 3.22(3H, s), 2.95 (6H, m), 2.58 (3H, s), 2.04 (3H, s), 1.77 (3H, d, J=6.5Hz) ppm.

Example 66.5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(25 mg, 0.061 mmol) (chiral pure, first peak from Example 20, Step 2),N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(25 mg, 0.091 mmol), sodium carbonate (13 mg, 0.12 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (II), complexwith dichloromethane (1:1) (9.9 mg, 0.012 mmol) in acetonitrile (0.8mL)/water (0.3 mL) was degassed with N₂ and then stirred at 95° C. for 2hours. After cooling to room temperature, the mixture was filtered andthe filtrate purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.05% trifluoroacetic acid, atflow rate of 30 mL/min) to give the desired product as bis-TFA salt. Theproduct was isolated as a single enantiomer. LCMS calculated forC₂₄H₂₇ClN₇O₂ (M+H)⁺: m/z=480.2; Found: 480.2. ¹H NMR (500 MHz, DMSO-d₆)δ: 8.78 (2H, br s), 8.48 (1H, m), 8.36 (1H, s), 7.86 (1H, br s), 7.65(1H, br s), 7.58 (1H, s), 6.33 (1H, q, J=7.0 Hz), 3.19 (3H, s), 3.03(3H, s), 2.97 (3H, s), 2.62 (3H, s), 2.06 (3H, s), 1.81 (3H, d, J=7.0Hz) ppm.

Example 67.1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1.1-[1-(3-Azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate(1.6 g, 3.2 mmol, from Example 13, Step 7) was treated with 4.0 Mhydrogen chloride in dioxane (8.15 mL, 32.6 mmol) in methylene chloride(17 mL) at room temperature for 2 h. The mixture was concentrated todryness to give the desired product. LCMS calculated for C₁₈H₂₁ClFN₆O(M+H)⁺: m/z=391.1; Found: 391.1.

Step 2.1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (0.90 g, 1.9 mmol, Example 67, step 1), acetone (1.0 mL,14 mmol) and triethylamine (2.5 mL, 18 mmol) in methylene chloride (20mL) was added sodium triacetoxyborohydride resin (2.5 g, 5.8 mmol). Themixture was stirred at room temperature for 2 h, then filtered, washedwith water, dried over MgSO₄, filtered and concentrated to give crudeproduct (870 mg, 100%). LCMS calculated for C₂₁H₂₇ClFN₆O (M+H)⁺:m/z=433.2; Found: 433.1.

Step 3. Single enantiomer of1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Enantiomers of1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(870 mg, 2.0 mmol) were separated on a Phenomenex Lux Cellulose-2column, eluting with 10% ethanol in hexanes, at flow rate of 18 mL/min,and column loading of ˜8 mg/injection to separate two enantiomers. Firstpeak retention time 10.9 min; second peak retention time 13.6 min. Thefractions of the 1st peak (110 mg, 13%) were concentrated and purifiedusing RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product. The product was isolated as asingle enantiomer. LCMS calculated for C₂₁H₂₇ClFN₆O (M+H)⁺: m/z=433.2;Found: 433.1.

Example 68.(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl)propan-2-ol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (15 mg, 0.032 mmol, from Example 67, Step 1) andtriethylamine (18 μL, 0.13 mmol) in ethanol (0.53 mL) was added(S)-(−)-methyloxirane (6.8 μL, 0.097 mmol). The resulting mixture washeated at 90° C. for 3 h, then purified on RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. Theenantiomers were separated on a Phenomenex Lux Cellulose C-4 column (5μM, 21.2×250 mm), eluting with 20% ethanol in hexanes, at flow rate of18 mL/min, to give two enantiomers. First peak (2.7 mg, 18%) retentiontime 8.9 min; LCMS calculated for C₂₁H₂₇ClFN₆O₂ (M+H)⁺: m/z=449.2;Found: 449.1. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.11 (1H, s), 7.42 (1H, d,J=8.5 Hz), 7.25 (2H, br s), 6.21 (1H, q, J=7.5 Hz), 4.28 (1H, d, J=4.0Hz), 3.82 (3H, m), 3.62 (3H, s), 3.55 (1H, m), 3.05 (1H, m), 2.97 (1H,m), 2.55 (3H, s), 2.28 (2H, m), 1.70 (2H, d, J=7.5 Hz), 1.00 (3H, d,J=6.0 Hz) ppm. Second peak retention time 10.0 min.

Example 71.2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl)ethanol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (19 mg, 0.041 mmol, racemic intermediate from Example67, Step 1) and triethylamine (28 μL, 0.20 mmol) in methanol (0.1mL)/acetonitrile (0.1 mL)/tetrahydrofuran (0.1 mL) was added{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (39 μL, 0.20 mmol),followed by sodium triacetoxyborohydride (22 mg, 0.10 mmol). Theresulting mixture was stirred overnight at room temperature. The mixturewas treated with 6.0 M hydrogen chloride in water (0.07 mL, 0.4 mmol) atroom temperature for 10 min and then purified on RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give the desiredproduct (2.5 mg, 13%). The product was isolated as a racemic mixture.LCMS calculated for C₂₀H₂₅ClFN₆O₂ (M+H)⁺: m/z=435.2; Found: 435.1.

Example 72.1-{1-[5-Chloro-4-fluoro-2-methoxy-3-(1-oxetan-3-ylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (19 mg, 0.041 mmol racemic intermediate from Example 67,Step 1) and triethylamine (28 μL, 0.20 mmol) in methanol (0.1mL)/acetonitrile (0.1 mL)/tetrahydrofuran (0.1 mL) was added 37%formaldehyde (15 μL, 0.20 mmol), followed by sodiumtriacetoxyborohydride (22 mg, 0.10 mmol). The resulting mixture wasstirred overnight at room temperature. The mixture was purified onRP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product (1.2 mg, 6.3%). The product wasisolated as a racemic mixture. LCMS calculated for C₁₉H₂₃ClFN₆O (M+H)⁺:m/z=405.2; Found: 405.1.

Example 73.1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1. tert-Butyl3-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate

To a mixture of tert-butyl3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate(0.77 g, 2.0 mmol, racemic intermediate from Example 13, Step 6,),3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.58 g, 2.2 mmol) inN,N-dimethylformamide (6.9 mL) was added potassium iodide (34 mg, 0.20mmol) and cesium carbonate (0.99 g, 3.0 mmol). The resulting mixture washeated at 140° C. and stirred for 3 h. After cooling, the clear solutionwas taken into water and ethyl acetate (EtOAc). The solid was dilutedwith water and EtOAc, and stirred until dissolved. The organic layerswere combined, concentrated and purified on silica gel (eluting with 0to 100% EtOAc in hexanes) to give the desired product (0.55 g, 45%).LCMS calculated for C₂₂H₂₆ClFIN₆O₃ (M+H)⁺: m/z=603.1; Found: 602.9.

Step 2. tert-Butyl3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate

To a solution of tert-butyl3-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate(0.55 g, 0.91 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(0.281 g, 1.82 mmol), sodium carbonate (0.580 g, 5.47 mmol) inN,N-dimethylformamide (5 mL)/water (2.73 mL) under N₂ was addedtetrakis(triphenylphosphine)-palladium(0) (0.105 g, 0.0910 mmol). Themixture was heated at 100° C. overnight. After cooling to roomtemperature, the mixture was diluted with water, and extracted withEtOAc. The combined organic layers were concentrated and purified onsilica gel (eluting with 0 to 100% EtOAc in hexanes followed by 0 to 10%MeOH in dichloromethane) to give the desired product (0.34 g, 74%). LCMScalculated for C₂₄H₂₉ClFN₆O₃ (M+H)⁺: m/z=503.2; Found: 503.1.

Step 3. tert-Butyl3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate

To a solution of tert-butyl3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate(340 mg, 0.680 mmol) in tert-butyl alcohol (5 mL) was addedN-methylmorpholine N-oxide (87 mg, 0.74 mmol) and water (2.1 mL). Tothis solution was then added 4% osmium tetraoxide (0.21 mL, 0.034 mmol).After stirring for 3 h, another equivalent of N-methylmorpholine N-oxidewas added. The reaction was stirred at room temperature overnight. Thesolution was diluted with water, and extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered and concentrated to givethe crude product (0.4 g, 100%) which was used directly in the nextstep. LCMS calculated for C₂₄H₃₁ClFN₆O₅(M+H)⁺: m/z=537.2; Found: 537.2.

Step 4. tert-Butyl3-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate

To a solution of tert-butyl3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate(0.40 g, 0.74 mmol) in tetrahydrofuran (5.6 mL)/water (3.4 mL) was addedacetic acid (0.011 mL, 0.19 mmol) and sodium periodate (0.478 g, 2.23mmol) at 0° C. After stirring for 2 h, the reaction mixture was dilutedwith water, and extracted with EtOAc. The organic layers were combined,washed with brine, dried over MgSO₄, filtered and concentrated to givethe desired product (0.35 g, 92%) which was used directly in the nextstep. LCMS calculated for C₂₃H₂₇ClFN₆O₄ (M+H)⁺: m/z=505.2; Found: 505.1.

Step 5. tert-Butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate

To a solution of tert-butyl3-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate(0.35 g, 0.69 mmol) in methylene chloride (4 mL) cooled at 0° C. wasadded dropwise diethylaminosulfur trifluoride (0.23 mL, 1.7 mmol). Themixture was stirred at room temperature for 2 h, then diluted withdichloromethane, washed with water, dried over MgSO₄, filtered thenconcentrated and purified on silica gel (eluting with 0 to 100% EtOAc inhexanes) to give the desired product (0.21 g, 57%). LCMS calculated forC₂₃H₂₇ClF₃N₆O₃ (M+H)⁺: m/z=527.2; Found: 527.2.

Step 6.1-[1-(3-Azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

tert-Butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate(0.21 g, 0.40 mmol) was treated with 4.0 M hydrogen chloride in dioxane(1 mL, 4 mmol) in methylene chloride (4 mL) at room temperature for 2 h.The mixture was concentrated to give the desired product (0.177 g, 89%).LCMS calculated for C₁₈H₁₉ClF₃N₆O (M+H)⁺: m/z=427.1; Found: 427.1.

Step 7.1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (45 mg, 0.090 mmol), acetone (37 mg, 0.63 mmol) andtriethylamine (63 μL, 0.45 mmol) in methylene chloride (0.9 mL) wasadded sodium triacetoxyborohydride resin (0.12 g, 0.27 mmol). Themixture was stirred at room temperature for 2 h, then filtered,concentrated and purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give the desired product (2.5 mg, 6.8%). Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₁H₂₅ClF₃N₆ (M+H)⁺: m/z=469.2; Found: 469.2.

Example 74.2-[3-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidin-1-yl]ethanol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (45 mg, 0.090 mmol),{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (110 mg, 0.63 mmol) andtriethylamine (63 μL, 0.45 mmol) in methylene chloride (0.9 mL) wasadded sodium triacetoxyborohydride resin (0.12 g, 0.27 mmol). Themixture was stirred at room temperature for 2 h, then filtered. Thefiltrate was treated with 6.0 M hydrogen chloride in water (0.2 mL, 0.9mmol), and purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give the desired product (2.5 mg, 5.6%). LCMScalculated for C₂₀H₂₃ClF₃N₆O₂ (M+H)⁺: m/z=471.1; Found: 471.2. Theracemic product was separated on a Phenomenex Lux Cellulose-4 column,eluting with 20% ethanol in hexanes, at flow rate of 18 mL/min, andcolumn loading of ˜4 mg/injection to separate two enantiomers. Firstpeak retention time 13.1 min; second peak retention time 16.3 min.

Example 76.(2S)-1-[3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidin-1-yl]propan-2-ol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (51 mg, 0.10 mmol, racemic intermediate from Example 73,Step 6) and triethylamine (57 μL, 0.41 mmol) in ethanol (1.7 mL) wasadded (S)-(−)-methyloxirane (18 μL, 0.26 mmol). The resulting mixturewas heated at 90° C. for 3 h, and purified on RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give the desiredproduct (2.7 mg, 5.3%). The product was isolated as a racemic mixture.LCMS calculated for C₂₁H₂₅ClF₃N₆O₂ (M+H)⁺: m/z=485.2; Found: 485.1.

Example 77.5-(1-(4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-fluoro-3-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-4-methoxybenzonitrile

To a microwave vial containing(2S)-1-[3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidin-1-yl]propan-2-ol(16 mg, 0.032 mmol, from Example 76) was added zinc (1.0 mg, 0.016mmol), bis(tri-t-butylphosphine)palladium (6.5 mg, 0.013 mmol) andN-methylpyrrolidinone (0.20 mL, 2.0 mmol). The mixture was degassed withN₂ for a few minutes before adding zinc cyanide (7.5 mg, 0.064 mmol).The resulting mixture was stirred at 130° C. overnight and then cooledand purified on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product (1.8 mg, 11.2%). The product wasisolated as a racemic mixture. LCMS calculated for C₂₂H₂₅F₃N₇O₂ (M+H)⁺:m/z=476.2; Found: 476.2.

Example 79.5-[3-(1-{4-Amino-3-[(3R)-3-hydroxybut-1-yn-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

A mixture of5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(9.8 mg, 0.016 mmol, racemic intermediate from Example 15) and copper(I)iodide (0.6 mg, 0.003 mmol) in N,N-dimethylformamide (0.32 mL) wastreated with (2R)-but-3-yn-2-ol (11.3 mg, 0.162 mmol), triethylamine(4.5 μL, 0.032 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (1.9mg, 0.0016 mmol) under N₂. The mixture was stirred under N₂ at roomtemperature for 1 h. The mixture was then purified on RP-HPLC (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.05% TFA, at flow rate of 30 mL/min) to give the desired product as abis-TFA salt (4.3 mg, 44%). The product was isolated as a racemicmixture. LCMS calculated for C₂₈H₃₁ClN₇O₃ (M+H)⁺: m/z=548.2; Found:548.1.

Example 80.5-[3-(1-{4-Amino-3-[(3S)-3-hydroxybut-1-yn-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

This compound was prepared using procedures analogous to Example 79,with (2S)-but-3-yn-2-ol replacing (2R)-but-3-yn-2-ol. The product wasisolated as a mixture of diastereomers. LCMS calculated for C₂₈H₃₁ClN₇O₃(M+H)⁺: m/z=548.2; Found: 548.1.

Example 81.5-{3-[1-(4-Amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Step 1.5-{3-[1-(4-Amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

To a solution of5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(130 mg, 0.21 mmol, racemic intermediate from Example 15),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (66 mg, 0.43 mmol),sodium carbonate (136 mg, 1.29 mmol) in N,N-dimethylformamide (1mL)/water (0.64 mL) under N₂ was addedtetrakis(triphenylphosphine)palladium(0) (25 mg, 0.021 mmol). Themixture was heated at 100° C. overnight. After cooling to roomtemperature, the mixture was diluted with water, and extracted withdichloromethane. The organic layers were concentrated and purified onsilica gel (eluting with 0 to 100% EtOAc in hexanes followed by 0 to 10%MeOH in dichloromethane) to give the desired product (94 mg, 86%). LCMScalculated for C₂₆H₂₉ClN₇O₂ (M+H)⁺: m/z=506.2; Found: 506.2.

Step 2.5-{3-[1-(4-Amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

5-{3-[1-(4-Amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(14 mg, 0.028 mmol) and 5% platinum on carbon (14 mg) was combined inmethanol (1 mL), to which was added 0.25 M hydrogen chloride in water(0.28 mL, 0.069 mmol). The suspension was hydrogenated under balloonpressure of H₂ at room temperature for 3 h. The suspension was filteredand the filtrate purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give the desired product (3.9 mg, 28%). Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₆H₃₁ClN₇O₂ (M+H)⁺: m/z=508.2; Found: 508.3.

Example 82.5-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

Step 1.5-(3-{1-[4-Amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

To a solution of5-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(80 mg, 0.16 mmol, from Example 81, Step 1) in tert-butyl alcohol (1 mL)was added N-methylmorpholine N-oxide (20 mg, 0.17 mmol) and water (0.50mL). To this solution was then added 4% osmium tetraoxide (5.0 μL,0.00079 mmol). After stirring for 3 h, another equivalent ofN-methylmorpholine N-oxide was added. The reaction was stirred at roomtemperature overnight. The solution was diluted with water, andextracted with EtOAc. The combined organic layers were dried over MgSO₄and filtered, concentrated to give the desired product (0.64 g, 95%).LCMS calculated for C₂₆H₃₁ClN₇O₄ (M+H)⁺: m/z=540.2; Found: 540.2.

Step 2.5-{3-[1-(4-Amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

To a solution of5-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide(70 mg, 0.13 mmol) in tetrahydrofuran (0.98 mL) and water (0.59 mL) wasadded acetic acid (1.9 μL, 0.034 mmol) and sodium periodate (83 mg, 0.39mmol) at 0° C. After stirring for 2 h, the reaction mixture was dilutedwith water, and extracted with dichloromethane. The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated to give the desired product (0.059 g, 90%). LCMS calculatedfor C₂₅H₂₇ClN₇O₃ (M+H)⁺: m/z=508.2; Found: 508.1.

Step 3.5-(3-{-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

To a solution of5-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(8.8 mg, 0.017 mmol) in methylene chloride (0.1 mL) cooled at 0° C. wasadded dropwise diethylaminosulfur trifluoride (5.7 μL, 0.043 mmol). Themixture was stirred at room temperature for 3 h, diluted with MeOH andpurified on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive the desired product as a bis-TFA salt (0.7 mg, 8%). The product wasisolated as a racemic mixture. LCMS calculated for C₂₅H₂₇ClF₂N₇O₂(M+H)⁺: m/z=530.2; Found: 530.0.

Example 83.5-(3-{1-[4-Amino-3-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

5-{3-[1-(4-Amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(5.6 mg, 0.011 mmol, from Example 82, Step 2) was treated with sodiumtetrahydroborate (0.5 mg, 0.01 mmol) in methanol (0.09 mL) at roomtemperature for 1 h. The mixture was purified on RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.05%TFA, at flow rate of 30 mL/min) to give the desired product as bis-TFAsalt (2.5 mg, 45%). The product was isolated as a racemic mixture. LCMScalculated for C₂₅H₂₉ClN₇O₃ (M+H)⁺: m/z=510.2; Found: 510.0.

Example 84.5-[3-(1-{4-Amino-3-[(methylamino)methyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

To a solution of5-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(8.8 mg, 0.017 mmol, from Example 82, Step 2) in methanol (1 mL) wasadded 2.0 M methylamine in THF (43 μL, 0.087 mmol). The mixture wasstirred at room temperature overnight before the addition of sodiumtetrahydroborate (1.3 mg, 0.035 mmol). The mixture was stirred at roomtemperature for 2 h, then diluted with MeOH and purified on RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 30 mL/min) to give the desiredproduct as TFA salt (4.2 mg, 48%). The product was isolated as a racemicmixture. LCMS calculated for C₂₆H₃₂ClN₈O₂ (M+H)⁺: m/z=523.2; Found:523.0.

Example 85.5-[3-(1-{4-Amino-3-[(dimethylamino)methyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamidetris(trifluoroacetate)

This compound was prepared using procedures analogous to Example 84,with 2.0 dimethylamine in THF replacing 2.0 M methylamine in THF. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₇H₃₄ClN₅O₂ (M+H)⁺: m/z=537.2; Found: 537.1.

Example 86.5-(3-{1-[4-Amino-3-(fluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

To a solution of5-(3-{1-[4-amino-3-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide(22 mg, 0.043 mmol, from Example 83) in methylene chloride (0.1 mL)cooled at 0° C. was added slowly2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (12μL, 0.065 mmol). The mixture was stirred at room temperature for 4 h,diluted with MeOH and purified on RP-HPLC (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.05% TFA, at flow rateof 30 mL/min) to give the desired product as TFA salt (3.9 mg, 18%). Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₅H₂₈ClFN₇O₂ (M+H)⁺: m/z=512.2; Found: 512.0.

Example 87.3-{1-[4-Amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

Step 1. 1-(5-Chloro-2-ethoxy-4-methyl-3-vinylphenyl)ethanone

A mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (1.1 g,3.2 mmol, from Example 14, Step 1),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.66 mL, 3.9 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.26 g, 0.32 mmol) and potassium carbonate(1.3 g, 9.4 mmol) in 1,4-dioxane (10 mL)/water (5 mL) was degassed withN₂ and heated at 80° C. overnight. After cooling to room temperature,the reaction mixture was extracted with EtOAc. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, concentratedand purified on silica gel (eluting with 0 to 10% EtOAc in hexanes) togive the desired product (0.64 g, 82%). LCMS calculated for C₁₃H₁₆ClO₂(M+H)⁺: m/z=239.1; Found: 239.1.

Step 2.1-[5-Chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-methylphenyl]ethanone

To a solution of 1-(5-chloro-2-ethoxy-4-methyl-3-vinylphenyl)ethanone(0.59 g, 2.5 mmol) in tert-butyl alcohol (20 mL) was addedN-methylmorpholine N-oxide (0.318 g, 2.72 mmol) and water (7.8 mL). Tothis solution was then added 4% osmium tetraoxide (0.078 mL, 0.012mmol). After 3 h, another equivalent of N-methylmorpholine N-oxide wasadded. The reaction was stirred for another 3 h. The solution wasdiluted with water, extracted with EtOAc. The combined organic layerswere dried over MgSO₄ and concentrated to give the desired product (0.64g, 95%). LCMS calculated for C₁₃H₁₇ClO₄Na (M+Na)⁺: m/z=295.1; Found:295.1.

Step 3. 3-Acetyl-5-chloro-2-ethoxy-6-methylbenzaldehyde

To a solution of1-[5-chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-methylphenyl]ethanone(0.64 g, 2.3 mmol) in tetrahydrofuran (18 mL) and water (11 mL) wasadded acetic acid (35 μL, 0.61 mmol) and sodium periodate (1.50 g, 7.04mmol) at 0° C. After stirring for 30 min, the reaction mixture wasdiluted with water, and extracted with EtOAc. The combined extracts werewashed with brine, dried over MgSO₄, filtered and concentrated to givethe desired product (0.58 g, 100%). LCMS calculated for C₁₂H₁₄ClO₃(M+H)⁺: m/z=241.1; Found: 241.1.

Step 4. 3-Acetyl-5-chloro-2-ethoxy-6-methylbenzoic acid

A solution of 3-acetyl-5-chloro-2-ethoxy-6-methylbenzaldehyde (0.58 g,2.4 mmol) and sodium phosphate monobasic monohydrate (116 mg, 0.844mmol) in acetonitrile (11.8 mL) and water (2.5 mL) was cooled in an icebath. 30% Hydrogen peroxide (0.98 mL, 9.6 mmol) was added followed bysolid sodium chlorite (0.545 g, 4.82 mmol). The mixture was stirred for1 h. The mixture was diluted with 1 M HCl solution, and extracted withEtOAc. The combined organic layers were dried over MgSO₄, filtered andconcentrated to give the desired product (0.67 g, 100%). LCMS calculatedfor C₁₂H₁₃ClO₄Na (M+Na)⁺: m/z=279.1; Found: 279.0.

Step 5. 3-Acetyl-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

To a solution of 3-acetyl-5-chloro-2-ethoxy-6-methylbenzoic acid (0.26g, 1.0 mmol) in N,N-dimethylformamide (5 mL) was addedbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.67 g, 1.5 mmol). After stirring for 10 min, N,N-diisopropylethylamine(0.35 mL, 2.0 mmol) and 2.0 M ethylamine in THF (2.5 mL, 5.1 mmol) wasadded. The resulting mixture was stirred at room temperature for 2 h.The reaction solution was diluted with water, and extracted withdichloromethane. The combined organic layers were concentrated andpurified on silica gel column (eluting with 0% to 50% EtOAc in hexanes)to give the desired product (0.2 g, 70%). LCMS calculated forC₁₄H₁₉ClNO₃ (M+H)⁺: m/z=284.1; Found: 284.1.

Step 6. 3-Chloro-6-ethoxy-N-ethyl-5-(1-hydroxyethyl)-2-methylbenzamide

3-Acetyl-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide (0.2 g, 0.7 mmol)was treated with sodium tetrahydroborate (0.032 g, 0.84 mmol) inmethanol (6 mL) at room temperature for 1 h. The mixture was dilutedwith water, extracted with dichloromethane. The combined organic layerswere dried over MgSO₄ and filtered, concentrated to give the desiredproduct. LCMS calculated for C₁₄H₂₁ClNO₃ (M+H)⁺: m/z=286.1; Found:286.1.

Step 7. 3-Chloro-5-(1-chloroethyl)-6-ethoxy-N-ethyl-2-methylbenzamide

A mixture of cyanuric chloride (0.15 g, 0.84 mmol) andN,N-dimethylformamide (0.065 mL, 0.84 mmol) was stirred at roomtemperature for 10 min and then a solution of3-chloro-6-ethoxy-N-ethyl-5-(1-hydroxyethyl)-2-methylbenzamide (0.16 g,0.56 mmol) in methylene chloride (3.1 mL) was added and the reaction wasstirred at room temperature overnight. The mixture was diluted withmethylene chloride, washed with water, concentrated and purified onsilica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desiredproduct (0.13 g, 76%). LCMS calculated for C₁₄H₂₀Cl₂NO₂ (M+H)⁺:m/z=304.1; Found: 304.1.

Step 8.3-[1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

A mixture of3-chloro-5-(1-chloroethyl)-6-ethoxy-N-ethyl-2-methylbenzamide (130 mg,0.43 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (120 mg, 0.47mmol), cesium carbonate (210 mg, 0.64 mmol) and potassium iodide (7.1mg, 0.043 mmol) in N,N-dimethylformamide (1 mL) was heated at 140° C.for 1 h. The mixture was diluted with ether, washed with water, andconcentrated. The residue was purified on silica gel (eluting with 0 to100% EtOAc in hexanes) to give the desired product (0.14 g, 62%). LCMScalculated for C₁₉H₂₃ClIN₆O₂ (M+H)⁺: m/z=529.1; Found: 528.9.

Step 9.3-{1-[4-Amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

To a solution of3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide(9.0 mg, 0.017 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.6 mg,0.034 mmol), sodium carbonate (11 mg, 0.10 mmol) inN,N-dimethylformamide (0.1 mL)/water (51 μL) under N₂ was addedtetrakis(triphenylphosphine)palladium(0) (2.0 mg, 0.0017 mmol). Themixture was heated at 100° C. overnight. After cooling to roomtemperature, the mixture was filtered and purified on RP-HPLC (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desiredproduct (0.9 mg, 10%). The product was isolated as a racemic mixture.LCMS calculated for C₂₂H₂₆ClN₅O₂ (M+H)⁺: m/z=469.2; Found: 469.0.

Example 88.3-{1-[4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

This compound was prepared using procedures analogous to Example 87,Step 9 (racemic intermediate), with (3-fluoro-5-hydroxyphenyl)boronicacid replacing4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The productwas isolated as a racemic mixture. LCMS calculated for C₂₅H₂₇ClFN₆O₃(M+H)⁺: m/z=513.2; Found: 513.0.

Example 89.3-(1-(4-Amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

This compound was prepared using procedures analogous to Example 87,Step 9 (racemic intermediate), with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-aminereplacing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.The product was isolated as a racemic mixture. LCMS calculated forC₂₆H₂₈ClN₈O₃ (M+H)⁺: m/z=535.2; Found: 535.0.

Example 90.3-{1-[4-Amino-3-(2-amino-1,3-benzothiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

This compound was prepared using procedures analogous to Example 87,Step 9 (racemic intermediate), with6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-aminereplacing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.The product was isolated as a racemic mixture. LCMS calculated forC₂₆H₂₈ClN₅O₂S (M+H)⁺: m/z=551.2; Found: 551.0.

Example 91.3-{1-[4-Amino-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

This compound was prepared using procedures analogous to Example 87,Step 9 (racemic intermediate), with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinereplacing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.The product was isolated as a racemic mixture. LCMS calculated forC₂₆H₂₈ClN₈O₂ (M+H)⁺: m/z=519.2; Found: 519.0.

Example 92.3-{1-[4-Amino-3-(1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

This compound was prepared using procedures analogous to Example 87,Step 9 (racemic intermediate), with6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole replacing4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The productwas isolated as a racemic mixture. LCMS calculated for C₂₆H₂₈ClN₈O₂(M+H)⁺: m/z=519.2; Found: 519.0.

Example 93.3-{1-[4-Amino-3-(1H-indol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

This compound was prepared using procedures analogous to Example 87,Step 9 (racemic intermediate), with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole replacing4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The productwas isolated as a racemic mixture. LCMS calculated for C₂₇H₂₉ClN₇O₂(M+H)⁺: m/z=518.2; Found: 518.0.

Example 94.1-{1-[5-Chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

Step 1. Benzyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate

A mixture of benzyl3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]azetidine-1-carboxylate(0.375 g, 0.888 mmol, from Example 35, Step 3),3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.16 g, 1.1 mmol), cesiumcarbonate (0.43 g, 1.3 mmol) and potassium iodide (15 mg, 0.089 mmol) inN,N-dimethylformamide (2.8 mL) was heated at 140° C. for 1 h. Themixture was diluted with ether, and washed with water. The organiclayers were concentrated and purified on silica gel (eluting with 0 to100% EtOAc in hexanes) to give the desired product (0.24 g, 50%). LCMScalculated for C₂₈H₃₂ClN₆O₃ (M+H)⁺: m/z=535.2; Found: 535.0. Theenantiomers were separated on a Phenomenex Lux Cellulose C-2 column (5μM, 21.2×250 mm), eluting with 20% ethanol in hexanes, at flow rate of18 mL/min, and column loading of ˜4.5 mg/injection to separate twoenantiomers. First peak retention time: 21.2 min; second peak retentiontime: 24.6 min.

Step 2.1-[1-(3-Azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Benzyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate(170 mg, 0.32 mmol, racemic intermediate) and 5% palladium (80 mg) werecombined in methanol (12 mL), to which was added 0.25 M hydrogenchloride in water (3.2 mL, 0.79 mmol). The suspension was hydrogenatedunder balloon pressure of H₂ at room temperature for 2 h. The suspensionwas filtered. The filtrate was neutralized with sat. NaHCO₃ solution,and extracted with dichloromethane. The combined organic layers weredried over MgSO₄ and filtered, concentrated to give the desired product(117 mg, 92%). LCMS calculated for C₂₀H₂₆ClN₆O (M+H)⁺: m/z=401.2; Found:401.1.

Step 3.1-{1-[5-Chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

Acetone (9.3 μL, 0.13 mmol) was added to1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(10.2 mg, 0.0254 mmol) in methanol (0.1 mL)/tetrahydrofuran (0.1mL)/acetonitrile (0.1 mL) and the mixture was stirred at roomtemperature for 10 min, before the addition of sodiumtriacetoxyborohydride (16 mg, 0.076 mmol). The reaction mixture wasstirred at room temperature for 4 h and then purified on RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 30 mL/min) to give the desiredproduct as TFA salt (2.3 mg, 22%). The product was isolated as a singleenantiomer. LCMS calculated for C₂₃H₃₂ClN₆O (M+H)⁺: m/z=443.2; Found:443.1.

Example 95.2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)ethanolbis(trifluoroacetate)

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(7.9 mg, 0.020 mmol, racemic intermediate from Example 94, Step 2) intetrahydrofuran (0.09 mL)/acetonitrile (0.09 mL)/methanol (0.09 mL) wasadded {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (19 μL, 0.098 mmol)and the mixture was stirred for 10 min before the addition of sodiumtriacetoxyborohydride (12 mg, 0.059 mmol). The resulting mixture wasstirred at room temperature for 4 h, then treated with 6.0 M hydrogenchloride in water (30 μL, 0.2 mmol) for 10 min. The mixture was purifiedon RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive the desired product as TFA salt (3.2 mg, 40%). The product wasisolated as a racemic mixture. LCMS calculated for C₂₂H₃₀ClN₆O₂ (M+H)⁺:m/z=445.2; Found: 445.1.

Example 96.(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)propan-2-olbis(trifluoroacetate)

Step 1. Benzyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate

The enantiomers from Example 94, Step 1 were separated on a PhenomenexLux Cellulose C-2 column (5 μM, 21.2×250 mm), eluting with 20% ethanolin hexanes, at flow rate of 18 mL/min, and column loading of ˜4.5mg/injection to separate two enantiomers. First peak retention time:21.2 min; second peak retention time: 24.6 min.

Step 2.1-[1-(3-Azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Benzyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate(chiral intermediate from first peak of previous step) was hydrogenatedin the presence of 5% palladium as described in Example 94, Step 2 togive the desired chiral product. LCMS calculated for C₂₀H₂₆ClN₆O (M+H)⁺:m/z=401.2; Found: 401.1.

Step 3.(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)propan-2-olbis(trifluoroacetate)

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(10 mg, 0.02 mmol, chiral intermediate from step 2) and triethylamine (9μL, 0.07 mmol) in isopropyl alcohol (0.05 mL) was added(S)-(−)-methyloxirane (4.5 μL, 0.064 mmol). The resulting mixture wasstirred at 90° C. overnight, cooled and purified on RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.05%TFA, at flow rate of 30 mL/min) to give the desired product as TFA salt(3.4 mg, 34%). The product was isolated as a single diastereomer. LCMScalculated for C₂₃H₃₂ClN₆O₂ (M+H)⁺: m/z=459.2; Found: 459.1.

Example 99.(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-oltrifluoroacetate

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(9.8 mg, 0.024 mmol, racemic intermediate from Example 94, Step 2),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (14 mg, 0.037 mmol) and triethylamine (10 μL, 0.073mmol) in N,N-dimethylformamide (0.15 mL) was added 85%(2S)-2-hydroxypropanoic acid in water (3.2 μL, 0.037 mmol). Theresulting mixture was stirred for 2 h at room temperature. The mixturewas purified on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive the desired product as trifluoroacetic acid (TFA) salt (2.9 mg,29%). The product was isolated as a racemic mixture. LCMS calculated forC₂₃H₃₀ClN₆O₃ (M+H)⁺: m/z=473.2; Found: 473.1.

Example 101.1-[1-(5-Chloro-2-ethoxy-4-methyl-3-{1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]azetidin-3-yl}phenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(9.6 mg, 0.024 mmol, racemic intermediate from Example 94, Step 2) andtriethylamine (10 μL, 0.072 mmol) in methylene chloride (0.2 mL) wasadded 1-methyl-1H-pyrazole-4-carbonyl chloride (5.2 mg, 0.036 mmol). Themixture was stirred at room temperature for 4 h, and evaporated to dryunder reduced pressure. The resultant residue was diluted with MeOH andpurified on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) togive the desired product as TFA salt (1.3 mg, 13%). The product wasisolated as a racemic mixture. LCMS calculated for C₂₅H₃₀ClN₅O₂ (M+H)⁺:m/z=509.2; Found: 509.1.

Example 102.(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (21 mg, 0.046 mmol) (Example 1, step 7, chiralintermediate from peak 1) and triethylamine (20 μL, 0.1 mmol) inisopropyl alcohol (0.10 mL) was added (S)-(−)-methyloxirane (3.2 μL,0.046 mmol). The resulting mixture was stirred at 90° C. After 90 min,additional (S)-(−)-methyloxirane (6.4 uL) was added and stirred at 90°C. overnight. After cooling, the mixture was diluted with methanol andpurified using RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give 6 mg (30%) of the product. The product was isolatedas a single diastereomer. LCMS calculated for C₂₂H₃₀ClN₆O₂ (M+H)⁺:m/z=445.2; Found: 445.2.

Example 104.2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)ethanol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (20 mg, 0.04 mmol) (Example 1, step 7, chiralintermediate from peak 1), {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde(8.3 mg, 0.048 mmol), and triethylamine (19 μL, 0.14 mmol) in methylenechloride (0.3 mL) was added sodium triacetoxyborohydride resin (38 mg,0.087 mmol). The resulting mixture was stirred overnight at roomtemperature. The mixture was filtered and concentrated. The crudeproduct was dissolved in tetrahydrofuran (1 mL) and cooled to 0° C. 1.0M Tetra-n-butylammonium fluoride in THF (0.44 mL, 0.44 mmol) was addedand warmed to room temperature. After 3 h, the solvents were evaporated.The crude was purified using RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give 8.1 mg (40%) of the desired product. Theproduct was isolated as a single enantiomer. LCMS calculated forC₂₁H₂₈ClN₆O₂ (M+H)⁺: m/z=431.2; Found: 431.3.

Example 105.(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (16 mg, 0.035 mmol, chiral intermediate from peak 1 ofExample 1, Step 7) and triethylamine (14 μL, 0.10 mmol) in acetonitrile(0.7 mL) was added bromoacetonitrile (2.7 μL, 0.038 mmol). The resultingmixture was stirred at room temperature for 2.5 h. The mixture wasdiluted with acetonitrile and purified by using RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.05%TFA, at flow rate of 30 mL/min) to give the desired product as the TFAsalt. The pure fractions were partially evaporated and then made basicby the addition of 1 N NaOH. The aqueous mixture was extracted withdichloromethane (2×). The extracts were dried (MgSO4), filtered, andconcentrated. The solid was dried in vacuo to give 6.9 mg (46%) of thedesired product. The product was isolated as a single enantiomer. LCMScalculated for C₂₁H₂₅ClN₇O (M+H)⁺: m/z=426.2; Found: 426.0.

Example 108.1-(1-{5-Chloro-2-methoxy-4-methyl-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (15 mg, 0.024 mmol, chiral intermediate from first peakof Example 1, step 7), 2,2,2-trifluoroethyl trifluoromethanesulfonate(6.8 mg, 0.029 mmol) and triethylamine (12 μL, 0.085 mmol) in methylenechloride (0.3 mL) was stirred over a weekend at room temperature. Thesolvents were evaporated and the crude purified using RP-HPLC (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 4.5 mg (39%)of the desired product. The product was isolated as a single enantiomer.LCMS calculated for C₂₁H₂₅ClF₃N₆ (M+H)⁺: m/z=469.2; Found: 469.1.

Example 110.(2R)-2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N-methylpropanamidetrifluoroacetate

A mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (26 mg, 0.067 mmol, chiral intermediate from peak 1 ofExample 1, Step 7), (2R)-2-bromopropanoic acid (7.3 μL, 0.081 mmol) andtriethylamine (19 μL, 0.13 mmol) in acetonitrile (0.8 mL) was stirredovernight at room temperature. The reaction was not complete so it washeated to 50° C. After 4 h, the solvents were evaporated. To the cruderesidue was added methylammonium chloride (4.5 mg, 0.067 mmol),N,N-dimethylformamide (0.2 mL), triethylamine (19 μL, 0.13 mmol), andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(45 mg, 0.10 mmol). The resulting mixture was stirred overnight at roomtemperature. The reaction mixture was added to a vial containing sat.NaHCO₃ and extracted with EtOAc (2×). The organics were dried (MgSO₄),filtered, and concentrated. The crude was purified using RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 30 mL/min) to give 1.4 mg (3.6%)of the desired product as the TFA salt. The product was isolated as asingle diastereomer. LCMS calculated for C₂₃H₃₁ClN₇O₂ (M+H)⁺: m/z=472.2;Found: 472.2.

Example 113.2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-3,3,3-trifluoropropan-1-ol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (20 mg, 0.04 mmol, chiral intermediate from peak 1 ofExample 1, step 7) and triethylamine (19 μL, 0.13 mmol) in acetonitrile(0.6 mL) was added 2-bromo-3,3,3-trifluoropropan-1-ol (from SynquestLabs, 9.2 mg, 0.048 mmol). N,N-dimethylformamide (0.3 mL) was added,which created a clear solution that was stirred at 70° C. overnight. Themixture was diluted water and purified using RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give 6.6 mg (30%) ofthe desired product. The product was isolated as a mixture ofdiastereomers. LCMS calculated for C₂₂H₂₇ClF₃N₆O₂ (M+H)⁺: m/z=499.2;Found: 499.1.

Example 115.(2R)-3-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1,1,1-trifluoropropan-2-ol

A mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (20 mg, 0.044 mmol, chiral intermediate from peak 1 ofExample 1, Step 7), (2R)-2-(trifluoromethyl)oxirane (9.4 μL, 0.11 mmol),and triethylamine (18 μL, 0.13 mmol) in ethanol (0.3 mL) was heated in amicrowave at 120° C. for 25 min. The mixture was diluted with MeOH andpurified by RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give 6.2 mg (28%) of the desired product. The product wasisolated as a single enantiomer. LCMS calculated for C₂₂H₂₇ClF₃N₆O₂(M+H)⁺: m/z=499.2; Found: 499.1.

Example 117.1-[1-(5-Chloro-2-methoxy-4-methyl-3-{1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]azetidin-3-yl}phenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (15 mg, 0.033 mmol) (chiral material, from Example 1,step 7, peak 1) and triethylamine (14 μL, 0.098 mmol) in methylenechloride (0.2 mL) was added 1-methyl-1H-pyrazole-4-carbonyl chloride(from Maybridge, 6.1 mg, 0.042 mmol). The resulting mixture was stirredovernight at room temperature. The solvents were evaporated and thecrude material was purified using RP-HPLC (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give 7.1 mg (44%) of theproduct. The product was isolated as a single enantiomer. LCMScalculated for C₂₄H₂₈ClN₈O₂ (M+H)⁺: m/z=495.2; Found: 495.2.

Example 118.(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (15 mg, 0.033 mmol, chiral intermediate from Example 1,Step 7, peak 1), mixture of (2S)-2-hydroxypropanoic acid (4.3 μL, 0.049mmol) (L-lactic acid, 85% aq.) and triethylamine (14 μL, 0.098 mmol) inN,N-dimethylformamide (0.2 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (19 mg, 0.049 mmol). The resulting mixture wasstirred overnight at room temperature. The mixture was diluted with MeOHand purified using RP-HPLC (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% ammonium hydroxide, at flow rateof 30 mL/min) to give 3.0 mg (20%) of the desired product. The productwas isolated as a single enantiomer. LCMS calculated for C₂₂H₂₈ClN₆O₃(M+H)⁺: m/z=459.2; Found: 459.2.

Example 121.(2R)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-oltrifluoroacetate

This compound was prepared using procedures analogous to those forExample 118 (starting from chiral material from Example 1, Step 7, peak1), with (R)-2-hydroxypropanoic acid instead of (2S)-2-hydroxypropanoicacid (4.3 μL, 0.049 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateinstead of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate. The crude was purified using RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.05%TFA, at flow rate of 30 mL/min) to give the desired product as the TFAsalt. The product was isolated as a single enantiomer. LCMS calculatedfor C₂₂H₂₈ClN₆O₃ (M+H)⁺: m/z=459.2; Found: 459.2.

Example 125.[3-(3-{1-[4-Amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidin-1-yl]acetonitrilebis(trifluoroacetate)

Step 1. tert-Butyl3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate

To a mixture of tert-butyl3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate(1.0 g, 2.7 mmol) (from Example 1, Step 5, racemic intermediate) and3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.629 g, 2.94 mmol) inN,N-dimethylformamide (8 mL) was added potassium iodide (44 mg, 0.27mmol) and cesium carbonate (1.30 g, 4.01 mmol). The resulting mixturewas heated to 120° C. and stirred for 4 h. After cooling, water wasadded and stirred briefly before the solids were filtered. The resultingsolids were washed with water, purified on silica gel (eluted with 0-10%MeOH in dichloromethane) to give 1.11 g (75%) of the desired product asa yellow gum. LCMS calculated for C₂₃H₂₉BrClN₆O₃ (M+H)⁺: m/z=551.1;Found: 551.1.

Step 2.1-[1-(3-Azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Trifluoroacetic acid (1.2 mL, 16 mmol) was added to a solution oftert-butyl3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate(224 mg, 0.407 mmol) in methylene chloride (2.5 mL) and stirred for 2 hat room temp. The mixture was diluted with dichloromethane and 1 N NaOHwas added and stirred rapidly for a few minutes. The layers wereseparated and the aqueous extracted with dichloromethane. The combinedorganics were dried (MgSO₄), filtered, and concentrated. Drying in vacuogave 163 mg (91%) of the freebase. LCMS calculated for C₁₈H₂₁BrClN₆O(M+H)⁺: m/z=451.1; Found: 451.0.

Step 3.(3-{3-[1-(4-Amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(100 mg, 0.2 mmol) and triethylamine (37 μL, 0.27 mmol) in acetonitrile(3 mL) was added bromoacetonitrile (19 μL, 0.27 mmol). The resultingmixture was stirred at room temp. After an hour, the reaction mixturewas still cloudy with not all of the material in solution. Several dropsof DMF were added which allowed for a clear solution. The mixture wasstirred overnight at room temperature and then most of the solvents wereevaporated. The resulting residue was purified on silica gel (elutedwith 0-10% MeOH in dichloromethane) to give 29 mg (30%) of the desiredproduct. LCMS calculated for C₂₀H₂₂BrClN₇O (M+H)⁺: m/z=490.1; Found:490.1.

Step 4.[3-(3-{1-[4-Amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidin-1-yl]acetonitrilebis(trifluoroacetate)

Into a microwave vial was added(3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile(14 mg, 0.029 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12mg, 0.058 mmol), tetrakis(triphenylphosphine)palladium(0) (3.4 mg,0.0029 mmol), N,N-dimethylformamide (0.15 mL), and 2.0 M sodiumcarbonate in water (73 μL, 0.14 mmol). The vial was capped and heated at100° C. for 3 h. The mixture was diluted with dichloromethane, filtered,and concentrated. The crude material was purified using RP-HPLC (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.05% TFA, at flow rate of 30 mL/min) to give 4.6 mg (22%) of theproduct as the TFA salt. The product was isolated as a racemic mixture.LCMS calculated for C₂₄H₂₇ClN₉O (M+H)⁺: m/z=492.2; Found: 492.1.

Example 126.[3-(3-{1-[4-Amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidin-1-yl]acetonitrile

Into a microwave vial was weighed1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(16 mg, 0.058 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.4mg, 0.0029 mmol). A solution of(3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile(14 mg, 0.029 mmol, racemic intermediate from Example 125, Step 3) inN,N-dimethylformamide (0.25 mL) was added followed by 2.0 M sodiumcarbonate in water (73 μL, 0.14 mmol). The resulting mixture was stirredat 120° C. for 5 h. The mixture was filtered and concentrated. To amixture of the crude coupling product in tetrahydrofuran (0.3 mL) wasadded 3.0 M hydrochloric acid solution in water (100 μL, 0.3 mmol) andstirred for 2 h at room temperature. The mixture was neutralized withsat. NaHCO₃ and extracted with dichloromethane. The organic was dried(MgSO₄), filtered, and concentrated. The crude was purified usingRP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give 1.0 mg (7.2% for 2 steps) of the desired product. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₃H₂₅ClN₉O (M+H)⁺: m/z=478.2; Found: 478.1.

Examples 127 and 128.1-{1-[5-Chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineand5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-(1-isopropylazetidin-3-yl)-4-methoxy-2-methylbenzonitrile

Step 1. tert-Butyl3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate

To a solution of tert-butyl3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate(1.1 g, 2.0 mmol, racemic intermediate from Example 125, Step 1) inN,N-dimethylformamide (10 mL) was addedtetrakis(triphenylphosphine)palladium(0) (230 mg, 0.20 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.68 mL, 4.0 mmol). 2.0M sodium carbonate in water (5.0 mL, 1.0 mmol) was added under N₂ andthe mixture heated at 100° C. for 3 h then stirred at room temperatureovernight. The reaction mixture was filtered through Celite, and washedwith EtOAc. The filtrates were washed with water and brine, dried(MgSO₄), filtered, and concentrated. The crude material was purified onsilica gel (eluted with 40-100% ethyl acetate in hexanes) to give 0.75 g(75%) of the desired product. LCMS calculated for C₂₅H₃₂ClN₆O₃ (M+H)⁺:m/z=499.2; Found: 499.0 (M+H); ¹H NMR (300 MHz, CDCl₃): δ 8.30 (s, 1H),7.50-7.40 (m, 1H), 6.99 (dd, J=17.7, 11.3 Hz, 1H), 6.44 (q, J=7.0 Hz,1H), 5.95 (dd, J=17.7, 1.3 Hz, 1H), 5.83 (br s, 1H), 5.65 (dd, J=11.3,1.3 Hz, 1H), 4.39-3.96 (m, 4H), 3.63 (d, J=6.7 Hz, 3H), 2.99-2.78 (m,1H), 2.22 (s, 4H), 1.84 (d, J=7.1 Hz, 3H), 1.43 (s, 9H).

Step 2. tert-Butyl3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

To a suspension of tert-butyl3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate(0.87 g, 1.7 mmol) in tert-butyl alcohol (11 mL) was addedN-methylmorpholine N-oxide (225 mg, 1.92 mmol), water (5.5 mL), andosmium tetraoxide (26 mg, 0.10 mmol). The resulting mixture was stirredovernight at room temp. Water was added to the reaction followed byEtOAc. The layers were separated and the aqueous extracted with EtOAc.The combined organics were washed with brine, dried (Na₂SO₄), filtered,and concentrated to give 0.93 g of the crude product. LCMS calculatedfor C₂₅H₃₄ClN₆O₅(M+H)⁺: m/z=533.2; Found: 533.2.

Step 3. tert-Butyl3-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate

To a solution of tert-butyl3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(0.93 g, 1.7 mmol) in tetrahydrofuran (13 mL) and water (8 mL) was addedacetic acid (26 μL, 0.45 mmol) and sodium periodate (1.12 g, 5.23 mmol)at 0° C. After stirring for 3 h with only slight warming, the reactionwas not yet complete so it was placed in the refrigerator overnight.Water was added to the reaction and extracted with dichloromethane (3×).The combined extracts were washed with brine, dried (Na₂SO₄), filtered,and concentrated. The crude was purified on silica gel (eluted with40-85% ethyl acetate in hexanes) to give 0.47 g (54%) of the desiredproduct. LCMS calculated for C₂₄H₃₀ClN₆O₄ (M+H)⁺: m/z=501.2; Found:501.3. ¹H NMR (300 MHz, CDCl₃) δ 10.05 (s, 1H), 8.37 (s, 1H), 7.39 (s,1H), 6.55 (q, J=7.1 Hz, 1H), 5.89 (s, 1H), 4.42-3.95 (m, 6H), 3.67 (s,3H), 2.25 (s, 3H), 1.90 (d, J=7.1 Hz, 3H), 1.44 (s, 9H) ppm.

Step 4. tert-Butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

To a solution of tert-butyl3-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate(0.96 g, 1.9 mmol) in methylene chloride (10 mL) stirring at 0° C. wasadded diethylaminosulfur trifluoride (0.63 mL, 4.8 mmol). The mixturewas stirred at 0° C. for a few minutes then warmed to room temp andstirred for 2.5 h. Water and dichloromethane were added and the layersseparated. The organic layer was washed with brine, dried (MgSO₄),filtered and concentrated. The crude was purified on silica gel (elutedwith 0-5% MeOH in dichloromethane) to give the desired product. LCMScalculated for C₂₄H₃₀ClF₂N₆O₃ (M+H)⁺: m/z=523.2; Found: 523.2.

Step 5.1-[1-(3-Azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

To a mixture of tert-butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(30 mg, 0.057 mmol) in dichloromethane (0.2 mL) was added 4.0 M hydrogenchloride in 1,4-dioxane (0.10 mL, 0.40 mmol). The resulting mixture wasstirred for 3 h at room temperature and then concentrated. The residuewas dried in vacuo to give 27 mg (100%) of the product as a salt. LCMScalculated for C₁₉H₂₂ClF₂N₆O (M+H)⁺: m/z=423.1; Found: 423.0.

Step 6.1-{1-[5-Chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (27 mg, 0.054 mmol), acetone (4.4 μL, 0.060 mmol), andtriethylamine (23.5 μL, 0.169 mmol) in methylene chloride (0.4 mL) wasadded sodium triacetoxyborohydride resin (47 mg, 0.11 mmol). Theresulting mixture was stirred for 2 h at room temperature. The mixturewas filtered and concentrated and dried in vacuo to give 22 mg of thecrude the product which will be used without purification. LCMScalculated for C₂₂H₂₈ClF₂N₆O (M+H)⁺: m/z=465.2; Found: 465.1.

Step 7.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-(1-isopropylazetidin-3-yl)-4-methoxy-2-methylbenzonitrile

0.5 mL of the preformed catalyst (from Example 40) was added to amixture of1-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(22 mg, 0.047 mmol), zinc (1.3 mg, 0.021 mmol) and zinc cyanide (5.6 mg,0.047 mmol) in N,N-dimethylacetamide (0.7 mL). The mixture was flushedwith N₂ and heated at 120° C. overnight. The reaction was about 50%complete and was stopped there so that both compounds could be isolated.The reaction mixture was filtered, washing with dichloromethane, andconcentrated. The crude was purified using RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give both title compounds. Theproducts were isolated as a racemic mixture. Example 126: Yield=6.6 mg(30%); LCMS calculated for C₂₂H₂₈ClF₂N₆O (M+H)⁺: m/z=465.2; Found:465.2; Example 127: Yield=3.0 mg (14%); LCMS calculated for C₂₃H₂₈F₂N₇O(M+H)⁺: m/z=456.2; Found: 456.2.

Example 129.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-4-methoxy-2-methyl-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]benzonitrile

Step 1. tert-Butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

Zinc (11 mg, 0.17 mmol) and bis(tri-t-butylphosphine)palladium (71 mg,0.14 mmol) were weighed into a microwave vial then a solution oftert-butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(182 mg, 0.348 mmol, racemic intermediate from Examples 127/128, step 4)in N-methylpyrrolidinone (2.0 mL) was added. The mixture was degassedwith N₂ for a few minutes before adding zinc cyanide (82 mg, 0.70 mmol).The resulting mixture was stirred at 130° C. for 3 h. After cooling, themixture was filtered through a pad of Celite and concentrated. The crudewas purified on silica gel, eluted with 0-5% MeOH in dichloromethane.The product eluted right away, along with NMP. The fractions werecombined and concentrated then taken up in EtOAc and washed with brine(3×). The organic was dried, filtered, and concentrated to give 0.17 g(96%) of the desired product. LCMS calculated for C₂₅H₃₀F₂N₇O₃ (M+H)⁺:m/z=514.2; Found: 514.1.

Step 2.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride

To a solution of tert-butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(0.20 g, 0.39 mmol) in methylene chloride (5 mL) was added 4.0 Mhydrogen chloride in 1,4-dioxane (0.60 mL, 2.4 mmol). The resultingmixture was stirred at room temp for 3.5 h. The solvents were evaporatedand the residue dried in vacuo to give 0.23 g of the product as the HClsalt. LCMS calculated for C₂₀H₂₂F₂N₇O (M+H)⁺: m/z=414.2; Found: 414.1.

Step 3.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-4-methoxy-2-methyl-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]benzonitrile

To a mixture of5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride (20 mg, 0.04 mmol) and triethylamine (20 μL, 0.14 mmol)in methylene chloride (0.3 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (11 mg, 0.049 mmol). The resulting mixture wasstirred at 40° C. for 3 h. The solvents were evaporated and the crudematerial purified using RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give 3.4 mg (20%) of the desired product. Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₂H₂₃F₅N₇O (M+H)⁺: m/z=496.2; Found: 496.1.

Example 130.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-[1-(2-hydroxyethyl)azetidin-3-yl]-4-methoxy-2-methylbenzonitrile

To a mixture of5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride (20 mg, 0.04 mmol, Example 129, Step 2),{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (9.1 μL, 0.048 mmol), andtriethylamine (19 μL, 0.14 mmol) in methylene chloride (0.3 mL) wasadded sodium triacetoxyborohydride resin (38 mg, 0.087 mmol). Theresulting mixture was stirred at room temperature for 3 h. The mixturewas filtered and concentrated. The crude product was dissolved intetrahydrofuran (1.0 mL) and 1.0 M tetra-n-butylammonium fluoride in THF(0.44 mL, 0.44 mmol) was added and stirred at room temperature. After1.5 h, the solvents were evaporated. The crude residue was purifiedusing RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give 4.1 mg (20%) of the desired product. The product wasisolated as a racemic mixture. LCMS calculated for C₂₂H₂₆F₂N₇O₂ (M+H)⁺:m/z=458.2; Found: 458.2.

Example 131.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-4-methoxy-2-methylbenzonitrile

To a mixture of5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride (20 mg, 0.04 mmol, racemic intermediate from Example129, Step 2) and triethylamine (18 μL, 0.13 mmol) in isopropyl alcohol(0.1 mL) was added (S)-(−)-methyloxirane (9.1 μL, 0.13 mmol). Theresulting mixture was stirred at 90° C. for 5 h. The crude mixture waspurified using RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to 2.5 mg (10%) of give the desired product. The product wasisolated as a mixture of diastereomers. LCMS calculated for C₂₃H₂₈F₂N₇O₂(M+H)⁺: m/z=472.2; Found: 472.2.

Example 133.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-[1-(2-hydroxy-2-methylpropyl)azetidin-3-yl]-4-methoxy-2-methylbenzonitrile

A mixture of5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride (21 mg, 0.043 mmol, racemic intermediate from Example129, Step 2), oxirane, 2,2-dimethyl- (11 μL, 0.13 mmol),N,N-diisopropylethylamine (19 μL, 0.11 mmol) and ethanol (0.5 mL) washeated in a microwave at 120° C. for 30 min. The crude mixture wasdiluted with acetonitrile and purified using RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give 6.1 mg (29%) ofthe desired product. The product was isolated as a racemic mixture. LCMScalculated for C₂₄H₃₀F₂N₇O₂ (M+H)⁺: m/z=486.2; Found: 486.2.

Example 134.(2S)-2-[3-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidin-1-yl]-N-methylpropanamide

Step 1.(2S)-2-[3-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidin-1-yl]propanoicacid

To a mixture of5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride (30 mg, 0.06 mmol, racemic intermediate from Example129, step 2) and methyl (2S)-2-chloropropanoate (7.9 μL, 0.074 mmol) inN,N-dimethylformamide (0.35 mL) was added potassium carbonate (26 mg,0.19 mmol). The resulting mixture was stirred at 60° C. overnight. Aftercooling, water was added and extracted with EtOAc (3×). The combinedextracts were dried (MgSO₄), filtered, and concentrated. To the cruderesidue was added methanol (0.3 mL), water (40 μL, 2 mmol), and lithiumhydroxide monohydrate (13 mg, 0.31 mmol). The resulting mixture wasstirred at room temperature for 2.5 h. The mixture was concentrated andused as is for the next reaction. LCMS calculated for C₂₃H₂₆F₂N₇O₃(M+H)⁺: m/z=486.2; Found: 486.2.

Step 2.(2S)-2-[3-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidin-1-yl]-N-methylpropanamide

To a mixture of(2S)-2-[3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidin-1-yl]propanoicacid (30 mg, 0.06 mmol), methylammonium chloride (6.6 mg, 0.098 mmol)and triethylamine (18 μL, 0.13 mmol) in N,N-dimethylformamide (0.3 mL)was added benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (43 mg, 0.098 mmol). The resulting mixture wasstirred for 3 h at room temperature. The mixture was diluted withacetonitrile, filtered, and purified using RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give 4.7 mg (10%, 3 steps) ofthe desired product. The product was isolated as mixture ofdiastereomers. LCMS calculated for C₂₄H₂₉F₂N₈O₂ (M+H)⁺: m/z=499.2;Found: 499.1.

Example 136.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-[1-(2,2-difluoroethyl)azetidin-3-yl]-4-methoxy-2-methylbenzonitrile

A mixture of5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride (21 mg, 0.043 mmol, racemic intermediate from Example129, Step 2), 2-bromo-1,1-difluoroethane (3.8 μL, 0.048 mmol), andtriethylamine (18 μL, 0.13 mmol) in N,N-dimethylformamide (0.3 mL) wasstirred overnight at 70° C. The mixture was diluted with methanol (MeOH)and purified using RP-HPLC (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% ammonium hydroxide, at flow rateof 30 mL/min) to give 3.3 mg (16%) of the desired product. The productwas isolated as a racemic mixture. LCMS calculated for C₂₂H₂₄F₄N₇O(M+H)⁺: m/z=478.2; Found: 478.1.

Example 137.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-4-methoxy-2-methylbenzonitrile

Step 1. tert-Butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

This compound was prepared using procedures analogous to Example 129,step 1, with the exception that the product was purified using aPhenomenex Lux-Cellulose 1 column (21.1×250 mm, 5 micron particle size),eluting with 10% ethanol in hexanes at a flow rate of 18 mL/min, 5mg/injection, to provide two enantiomers. For Peak 1: retention time:1.12 min; LCMS calculated for C₂₅H₃₀F₂N₇O₃ (M+H)⁺: m/z=514.2; Found:514.1. Peak 2 retention time was 2.58 min.

Step 2.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride

This compound was prepared using procedures analogous to Example 128,step 2, with tert-butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(peak 1 from step 1) instead of tert-butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidine-1-carboxylate.LCMS calculated for C₂₀H₂₂F₂N₇O (M+H)⁺: m/z=414.2; Found: 414.1.

Step 3.5-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-4-methoxy-2-methylbenzonitrile

To a mixture of5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride (25 mg, 0.051 mmol),(2S)-2-{[tert-butyl(diphenyl)silyl]oxy}propanal (18 mg, 0.057 mmol) andtriethylamine (22 μL, 0.15 mmol) in methylene chloride (0.3 mL) wasadded sodium triacetoxyborohydride resin (45 mg, 0.10 mmol). The mixturewas stirred overnight then filtered and concentrated. To the residue wasadded tetrahydrofuran (1.0 mL) and 1.0 M tetra-n-butylammonium fluoridein THF (0.51 mL, 0.51 mmol). The resulting mixture was stirred overnightat room temp. The solvent was evaporated and the crude material waspurified using RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give 1.6 mg (6.6%) of the desired product. The product wasisolated as a single diastereomer. LCMS calculated for C₂₃H₂₈F₂N₇O₂(M+H)⁺: m/z=472.2; Found: 472.2.

Example 138.3-(1-Acetylazetidin-3-yl)-5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-4-methoxy-2-methylbenzonitrile

A mixture of5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitriledihydrochloride (21 mg, 0.043 mmol, racemic intermediate from Example129, Step 2), acetyl chloride (3.4 μL, 0.048 mmol), and triethylamine(18 μL, 0.13 mmol) in methylene chloride (0.3 mL) was stirred overnightat room temperature. The solvents were evaporated and the crude materialwas purified using RP-HPLC (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% ammonium hydroxide, at flow rateof 30 mL/min) to give the desired product. The product was isolated as aracemic mixture. LCMS calculated for C₂₂H₂₄F₂N₇O₂ (M+H)⁺: m/z=456.2;Found: 456.2.

Example 139. Enantiomers of1-{1-[5-Chloro-2-ethoxy-4-fluoro-3-(1-isopropylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1. 1-(5-Chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone

This compound was prepared according to the procedure of Example 13 Step3, using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone andiodoethane as the starting materials. LCMS calculated for C₁₀H₁₀ClFIO₂(M+H)⁺: m/z=342.9; Found: 342.9.

Step 2. tert-Butyl3-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate

A round-bottom flask equipped with a magnetic stir bar and a rubberseptum was charged with lithium chloride (3.9 g, 91 mmol). The flask washeated at 140° C. for 10 min under high vacuum and backfilled withnitrogen after cooling to room temperature. Zinc (6.0 g, 91 mmol) wasadded and the flask was heated at 140° C. for 10 min under high vacuumand backfilled with nitrogen after cooling to room temperature.Tetrahydrofuran (THF) (38 mL) and 1,2-dibromoethane (233 μL, 2.70 mmol)were added via syringe. The mixture was heated at 60° C. for 10 min andthen cooled to room temperature. Chlorotrimethylsilane (68 μL, 0.54mmol) and iodine (69 mg, 0.27 mmol) in THF (1 mL) were added and theresulting mixture was stirred at 60° C. for 10 min then cooled to roomtemperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate(12.17 g, 42.99 mmol) in THF (10 mL) was then added and the mixturestirred at 40° C. for 1 h and at room temperature for 1 h. Another flaskcharged with 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (13.0g, 38.0 mmol), palladium acetate (170 mg, 0.76 mmol),2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine(660 mg, 1.5 mmol), and toluene (35 mL) was evacuated under high vacuumand backfilled with nitrogen. The mixture was cooled to 0° C. and thezinc reagent made above was added slowly via syringe. After addition,the reaction was heated to 50° C. overnight. The reaction solution waspartitioned between EtOAc and sat. NH₄Cl solution. The layers wereseparated and the aqueous extracted further with EtOAc (2×). Thecombined organics were washed with water, brine, then dried over MgSO4,and concentrated. The crude mixture was purified on silica gel column togive the desired product as an orange oil (6.3 g, 45%). LCMS calculatedfor C₁₈H₂₃ClFNO₄Na (M+Na)⁺: m/z=394.1; Found: 394.1.

Step 3. tert-Butyl3-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate

This compound was prepared according to the procedure of Example 13 Step5, using tert-butyl3-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate andsodium tetrahydroborate as the starting materials. LCMS calculated forC₁₈H₂₅ClFNO₄Na (M+Na)⁺: m/z=396.1; Found: 396.1.

Step 4. tert-Butyl3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]azetidine-1-carboxylate

This compound was prepared according to the procedure of Example 13 step6, using tert-butyl3-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate(racemic) and cyanuric chloride as the starting materials.

Step 5. tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate

To a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.10 g,7.37 mmol), cesium carbonate (3.2 g, 10 mmol) and potassium iodide (111mg, 0.670 mmol) in DMF (20 mL) was added tert-butyl3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]azetidine-1-carboxylate(2.63 g, 6.70 mmol) and the mixture was stirred at 90° C. for 3 h. Thesolvent was removed in vacuo. The residue was diluted with ethyl acetateand water. Aqueous layer was extracted with ethyl acetate twice. Thecombined organic layers were washed with water, brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified on silicagel column (eluting with 100% ethyl acetate) to give the desired productas a foam (2.15 g, 63%). LCMS calculated for C₂₄H₃₁ClFN₆O₃ (M+H)⁺:m/z=505.2; Found: 505.2.

Step 6.1-[1-(3-Azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

To a solution of tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate(275 mg, 0.544 mmol) in dichloromethane (2.4 mL) was added 4.0 Mhydrogen chloride in dioxane (1.1 mL, 4.4 mmol). The reaction solutionwas stirred at room temperature for 6 h. The solvent was removed underreduced pressure to give the desired product as a white solid (250 mg,96%). LCMS calculated for C₁₉H₂₃ClFN₆O (M+H)⁺: m/z=405.2; Found: 405.1.

Step 7.1-{1-[5-Chloro-2-ethoxy-4-fluoro-3-(1-isopropylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (49 mg, 0.10 mmol), acetone (8.28 μL, 0.113 mmol), andtriethylamine (44.3 μL, 0.318 mmol) in dichloromethane (0.67 mL) wasadded sodium triacetoxyborohydride resin (89 mg, 0.20 mmol). Theresulting mixture was stirred overnight at room temperature. The mixturewas filtered and concentrated and then purified by preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 60 mL/min) to give the racemicproduct. LCMS: found m/z=447.2 (M+H)⁺. The racemic mixture was separatedby chiral HPLC (column IA, eluting with 5% ethanol/95% hexanes, at flowrate 18 mL/min) to give two peaks (isomer 1: 9.5 mg, 21%; isomer 2: 9.2mg, 20%).

Isomer 1 (first to elute, retention time: 4.4 min): ¹H NMR (400 MHz,DMSO-d₆): δ□ 8.10 (s, 1H), 7.45 (d, 1H), 6.21 (m, 1H), 3.70 (m, 5H),2.91 (m, 2H), 2.53 (s, 3H), 2.17 (m, 1H), 1.66 (d, 3H), 1.31 (t, 3H),0.81 (m, 6H) ppm; LCMS calculated for C₂₂H₂₉ClFN₆O (M+H)⁺: m/z=447.2;Found: 447.2. Isomer 2 (second to elute, retention time: 19.5 min): LCMScalculated for C₂₂H₂₉ClFN₆O (M+H)⁺: m/z=447.2; Found: 447.2.

Example 140.1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)-2-methylpropan-2-ol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (20 mg, 0.042 mmol, racemic intermediate from Example139, Step 6) and triethylamine (18 μL, 0.12 mmol) in ethanol (1 mL) wasadded oxirane, 2,2-dimethyl- (6.98 μL, 0.0837 mmol). The resultingmixture was heated at 120° C. in microwave reactor for 45 min. Thereaction was diluted with methanol and purified on RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give the desiredproduct as white a solid (3.4 mg, 17%). The product was isolated as aracemic mixture. LCMS calculated for C₂₃H₃₁ClFN₆O₂ (M+H)⁺: m/z=477.2;Found: 477.3.

Example 1411-(1-{5-Chloro-2-ethoxy-4-fluoro-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (19 mg, 0.040 mmol, racemic intermediate from Example139, Step 6) and triethylamine (20 μL, 0.14 mmol) in dichloromethane(0.5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11mg, 0.048 mmol). The resulting mixture was stirred overnight at roomtemperature. The solvents were evaporated under reduced pressure and thecrude mixture purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give the desired product (3.8 mg, 19%). Theproduct was isolated as a racemic mixture. LCMS calculated forC₂₁H₂₄ClF₄N₆O (M+H)⁺: m/z=487.2; Found: 487.1.

Example 149(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol

Step 1. Enantiomers of tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate

The racemic mixture was separated by chiral HPLC (column IA, elutingwith 5% ethanol/95% hexanes, flow rate 18 mL/min) to give two peaks;Isomer 1 (first to elute): Retention time: 16.8 min; LCMS calculated forC₂₄H₃₁ClFN₆O₃ (M+H)⁺: m/z=505.2; Found: 505.2; Isomer 2 (second toelute): Retention time: 19.5 min; LCMS calculated for C₂₄H₃₁ClFN₆O₃(M+H)⁺: m/z=505.2; Found: 505.2.

Step 21-[1-(3-Azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

This compound was prepared using procedures analogous to those forExample 139 step 6 with tert-butyl3-{3-[(1S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate(first peak from chiral separation) as starting material. LCMScalculated for C₁₉H₂₃ClFN₆O (M+H)⁺: m/z=405.2; Found: 405.1.

Step 3.(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol

To a mixture of1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (46 mg, 0.11 mmol) (from isomer 1) and triethylamine (50μL, 0.4 mmol) in isopropyl alcohol (0.3 mL) was added(S)-(−)-methyloxirane (16 μL, 0.23 mmol). The resulting mixture wasstirred at 90° C. for 3 h. After cooling, the mixture was diluted withacetonitrile and purified by RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give the desired product (12 mg, 23%). Theproduct was isolated as a single diastereomer. ¹H NMR (400 MHz,DMSO-d₆): δ 8.05 (s, 1H), 7.38 (d, 1H), 6.15 (m, 1H), 4.26 (d, 1H),3.76-3.60 (m, 6H), 2.99 (m, 2H), 2.48 (s, 3H), 2.22 (m, 2H), 1.62 (d,3H), 1.25 (t, 3H), 0.93 (d, 3H) ppm; LCMS calculated for C₂₂H₂₉ClFN₆O₂(M+H)⁺: m/z=463.2; Found: 463.2.

Example 1501-{1-[5-Chloro-2-ethoxy-4-fluoro-3-(1-isopropylazetidin-3-yl)phenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1: tert-Butyl3-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 139 step 5, with racemic tert-butyl3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]azetidine-1-carboxylatefrom Example 139 Step 4 and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineas starting materials. LCMS calculated for C₂₃H₂₈ClFIN₆O₃ (M+H)⁺:m/z=617.1; Found: 617.1.

Step 2 tert-Butyl3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate

A mixture of tert-butyl3-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate(1.32 g, 2.14 mmol), pyridine-trivinylboroxin (1:1) (0.51 g, 2.1 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (90 mg, 0.1 mmol) and potassium carbonate(0.89 g, 6.4 mmol) in 1,4-dioxane (10 mL)/water (7 mL) was heated at100° C. overnight. After cooled to room temperature, the reactionmixture was diluted with water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate. The combined extracts were washed withbrine, dried over MgSO₄, concentrated and purified on a silica gelcolumn to give the desired product (0.71 g, 64%). LCMS calculated forC₂₅H₃₁ClFN₆O₃ (M+H)⁺: m/z=517.2; Found: 517.2.

Step 3. tert-Butyl3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate

To a suspension of tert-butyl3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate(0.707 g, 1.37 mmol) in tert-butyl alcohol (8.6 mL) was addedN-methylmorpholine N-oxide (176 mg, 1.50 mmol), water (4.3 mL), andosmium tetraoxide (20 mg, 0.080 mmol). The resulting mixture was stirredovernight at room temperature. Water was added to the reaction followedby EtOAc. The layers were separated and the aqueous extracted withEtOAc. The combined organics were washed with brine, dried over Na₂SO₄,filtered, and concentrated to give the crude product. LCMS calculatedfor C₂₅H₃₃ClFN₆O₅(M+H)⁺: m/z=551.2; Found: 551.2.

Step 4. tert-Butyl3-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate

To a solution of tert-butyl3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate(0.754 g, 1.37 mmol) in THF (10 mL) and water (6 mL) was added aceticacid (20 μL, 0.36 mmol) and sodium periodate (0.878 g, 4.10 mmol) at 0°C. After stirring overnight, water was added to the reaction andextracted with dichloromethane (3×). The combined extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated to yield thecrude product. LCMS calculated for C₂₄H₂₉ClFN₆O₄ (M+H)⁺: m/z=519.2;Found: 519.2.

Step 5. tert-Butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate

To a solution of tert-butyl3-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate(0.61 g, 1.2 mmol) in dichloromethane (7 mL) at 0° C. was addeddiethylaminosulfur trifluoride (0.39 mL, 2.9 mmol). The mixture wasstirred at 0° C. for a few minutes then warmed to room temperature andstirred for 2.5 h. Water and dichloromethane were added and the layersseparated. The organics were washed with brine, dried over MgSO₄,filtered and concentrated. The yellow gum was dried in vacuo to give thedesired product (0.60 g, 94%). LCMS calculated for C₂₄H₂₉ClF₃N₆O₃(M+H)⁺: m/z=541.2; Found: 541.2.

Step 6.1-[1-(3-Azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

To a solution of tert-butyl3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate(0.64 g, 1.2 mmol) in dichloromethane (5 mL) was added 4.0 M hydrogenchloride in dioxane (2.4 mL, 9.5 mmol). The reaction solution wasstirred at room temperature for 6 h. The solvent was removed to give thedesired product as a white solid (0.61 g, 100%). LCMS calculated forC₁₉H₂₁ClF₃N₆O (M+H)⁺: m/z=441.1; Found: 441.1.

Step 7.1-{1-[5-Chloro-2-ethoxy-4-fluoro-3-(1-isopropylazetidin-3-yl)phenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

This compound was prepared using procedures analogous to those forExample 1 step 8, with1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride and acetone as starting materials. The product wasisolated as a racemic mixture. LCMS calculated for C₂₂H₂₇ClF₃N₆O (M+H)⁺:m/z=483.2; Found: 483.2.

Example 1522-[3-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidin-1-yl]ethanol

This compound was prepared using procedures analogous to those forExample 1 step 8, with1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (racemic) and{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde as starting materials.After reductive amination, tetrabutylammonium fluoride was added toremove the tert-butyl(dimethyl)silyl group. The product was isolated asa racemic mixture. LCMS calculated for C₂₁H₂₅ClF₃N₆O₂ (M+H)⁺: m/z=485.2;Found: 485.2. ¹H NMR (300 MHz, DMSO-d₆): δ 8.23 (s, 1H), 7.38 (m, 2H),6.29 (m, 1H), 3.78-3.67 (m, 4H), 3.53 (m, 1H), 3.12 (m, 2H), 2.99-2.87(m, 2H), 2.34 (m, 2H), 1.68 (d, 3H), 1.22 (m, 3H) ppm.

Example 156(2R)-2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-1-ol

Step 1. Methyl (2S)-2-bromopropanoate

DMF (28 μL, 0.36 mmol) was added to a mixture of (2S)-2-bromopropanoicacid (0.552 g, 3.61 mmol) and oxalyl chloride (0.61 mL, 7.2 mmol) indichloromethane (4.6 mL) at 0° C. The reaction mixture was stirred atroom temperature overnight. The solvent was removed in vacuo. Theresidue was dissolved in dichloromethane and treated with methanol (1.5mL, 36 mmol) and pyridine (0.44 mL, 5.4 mmol). The reaction solution wasstirred at room temperature for 2 h. The reaction solution was quenchedwith saturated sodium bicarbonate solution and washed with brine, driedover Na₂SO₄, filtered and concentrated to give the desired product (0.51g, 85%).

Step 2. Methyl(2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoate

To a solution of1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminehydrochloride (20.1 mg, 0.0475 mmol, chiral intermediate from Example 1,Step 7) in acetonitrile (1 mL) was added triethylamine (23 μL, 0.17mmol) and methyl (2S)-2-bromopropanoate (9.5 mg, 0.057 mmol). Thereaction solution was stirred at room temperature for 4 h. The solventwas removed to give the desired product (6.2 mg, 28%). LCMS calculatedfor C₂₃H₃₀ClN₆O₃ (M+H)⁺: m/z=473.2; Found: 473.3.

Step 3.(2R)-2-(3-{3-[(1S)-1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-1-ol

A solution of methyl(2R)-2-(3-{3-[(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoate(6.2 mg, 0.013 mmol) in dichloromethane (0.5 mL) was treated with 1.0 Mdiisobutylaluminum hydride in toluene (0.1 mL, 0.1 mmol) at 0° C. for 3h. The reaction was quenched with methanol and purified with preparativeRP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product (0.8 mg, 14%). The product wasisolated as a single diastereomer. LCMS calculated for C₂₂H₃₀ClN₆O₂(M+H)⁺: m/z=445.2; Found: 445.1.

Example 1581-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-2-methylpropan-2-ol

This compound was prepared using procedures analogous to t Example 140with1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminehydrochloride (chiral intermediate from Example 1, Step 7) and oxirane,2,2-dimethyl- as starting materials. The product was isolated as singleenantiomer. LCMS calculated for C₂₃H₃₂ClN₆O₂ (M+H)⁺: m/z=459.2; Found:459.1 ¹H NMR (300 MHz, DMSO-d₆): δ 8.04 (s, 1H), 7.23 (bs, 2H), 7.16 (s,1H), 6.14 (m, 1H), 3.96 (s, 1H), 3.85 (m, 3H), 3.45 (s, 3H), 2.94 (m,1H), 2.80 (m, 1H), 2.49 (s, 3H), 2.14 (s, 2H), 2.00 (s, 3H), 1.63 (d,3H), 0.98 (s, 6H) ppm.

Example 159(2R)-2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N,N-dimethylpropanamide

Step 1.(2R)-2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoicacid

To a solution of methyl(2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoate(chiral intermediate from example 156 step 2) (13 mg, 0.027 mmol) inacetonitrile (0.6 mL) and water (0.2 mL) was added lithium hydroxide(2.4 mg, 0.10 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction solution was diluted with ethylacetate and 1 M HCl solution. The organic layer was separated and driedover Na₂SO₄, filtered and concentrated to give the desired product (10.2mg, 83%). LCMS calculated for C₂₂H₂₈ClN₆O₃ (M+H)⁺: m/z=459.2; Found:459.1.

Step 2.(2R)-2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N,N-dimethylpropanamide

To a solution of(2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoicacid (4 mg, 0.009 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(4 mg, 0.009 mmol) in DMF (0.3 mL) at room temperature was addedtriethylamine (4 μL, 0.03 mmol) and dimethylamine hydrochloride (0.9 mg,0.01 mmol). The reaction mixture was stirred for 1 h, then diluted withmethanol and purified by preparative RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product (2.7mg, 63%). The product was isolated as a single diastereomer. LCMScalculated for C₂₄H₃₃ClN₇O₂ (M+H)⁺: m/z=486.2; Found: 486.1. ¹H NMR (300MHz, DMSO-d₆): δ□ 8.09 (s, 1H), 7.23 (s, 1H), 6.18 (m, 1H), 3.78 (m,3H), 3.50 (s, 3H), 3.01 (s, 3H), 3.0-2.9 (m, 3H), 2.77 (s, 3H), 2.54 (s,3H), 2.06 (s, 3H), 1.67 (d, 3H), 0.98 (d, 3H) ppm.

Example 161[1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)cyclobutyl]acetonitrile

To a solution of1-[(1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (10 mg, 0.022 mmol, chiral intermediate from Example 1,Step 7) in acetonitrile (0.1 mL) was added cyclobutylideneacetonitrile(4.1 mg, 0.044 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (13μL, 0.087 mmol). The resulting mixture was stirred at room temperatureovernight. The reaction mixture was diluted with acetonitrile andpurified by preparative RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give the desired product (4.3 mg, 41%). Theproduct was isolated as a single enantiomer. LCMS calculated forC₂₅H₃₁ClN₇O (M+H)⁺: m/z=480.2; Found: 480.0.

Example 1631-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1. tert-Butyl4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 139 step 2 with1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone and tert-butyl4-iodopiperidine-1-carboxylate as starting materials. LCMS calculatedfor C₂₀H₂₈ClNO₄Na (M+Na)⁺: m/z=404.1; Found: 404.1.

Step 2. tert-Butyl4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate

This compound was prepared according to the procedure of Example 13 step5, using of tert-butyl4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)piperidine-1-carboxylateand sodium tetrahydroborate as the starting materials. LCMS calculatedfor C₂₀H₃₀ClNO₄Na (M+Na)⁺: m/z=406.1; Found: 406.1.

Step 3. tert-Butyl4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate

This compound was prepared according to the procedure of Example 13 step6, using tert-butyl4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate(racemic) and cyanuric chloride as the starting materials. ¹H NMR (400MHz, CDCl₃): δ 7.44 (s, 1H), 5.46 (m, 1H), 4.23 (bs, 2H), 3.73 (s, 3H),3.29 (bs, 1H), 2.78 (bs, 2H), 2.40 (s, 3H), 2.27-2.09 (m, 2H), 1.78 (d,3H), 1.63 (m, 2H), 1.43 (s, 9H) ppm.

Step 4. tert-Butyl4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidine-1-carboxylate

This compound was prepared according to the procedure of Example 139step 5, using of tert-butyl4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylateand 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as the startingmaterials. LCMS calculated for C₂₆H₃₆ClN₆O₃ (M+H)⁺: m/z=515.3; Found:515.2.

Step 5.1-[1-(5-Chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride

This compound was prepared according to the procedure of Example 139step 6, using of tert-butyl4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidine-1-carboxylateas the starting material. LCMS calculated for C₂₁H₂₈ClN₆O (M+H)⁺:m/z=415.2; Found: 415.2.

Step 6.1-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

This compound was prepared according to the procedure of Example 139step 7, using of1-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride and formaldehyde as the starting materials. The productwas isolated as a racemic mixture. LCMS calculated for C₂₂H₃₀ClN₆O(M+H)⁺: m/z=429.2; Found: 429.1.

Example 1641-(4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidin-1-yl)-2-methylpropan-2-ol

This compound was prepared using procedures analogous to those forExample 140 with1-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminedihydrochloride (racemic intermediate from Example 163, Step 5) andoxirane, 2,2-dimethyl- as starting materials. The product was isolatedas a racemic mixture. LCMS calculated for C₂₅H₃₆ClN₆O₂ (M+H)⁺:m/z=487.3; Found: 487.3. ¹H NMR (300 MHz, DMSO-d₆): δ 8.05 (s, 1H), 7.24(bs, 2H), 7.22 (s, 1H), 6.16 (m, 1H), 4.01 (bs, 1H), 3.67 (s, 3H), 2.97(m, 3H), 2.49 (s, 3H), 2.32 (s, 3H), 2.15-2.04 (m, 6H), 1.63 (d, 3H),1.40 (m, 2H), 1.03 (s, 6H) ppm.

Example 1655-(3-{1-[4-Amino-3-(cyanomethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

This compound was prepared according to the procedure described inExample 47, using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (from Frontier)instead of (3-fluorophenyl)boronic acid. The product was isolated as aracemic mixture. LCMS calculated for C₂₆H₂₈ClN₈O₂ (M+H)⁺: m/z=519.2;Found: 519.2.

Example 1663-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}cyclobutanoltrifluoroacetate

Step 1. 1-(5-Chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanone

A mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (1.0g, 3.2 mmol, from Example 1, Step 2),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.66 mL, 3.9 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.26 g, 0.32 mmol) and potassium carbonate(1.3 g, 9.4 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was degassedwith N₂ and heated at 80° C. overnight. After cooled to roomtemperature, the reaction mixture was diluted with water and ethylacetate. The organic layer was washed with brine, dried over MgSO₄,concentrated and purified on a silica gel column (eluting with 0 to 10%EtOAc in hexanes) to give the desired product (0.60 g, 82%). LCMScalculated for C₁₂H₁₄ClO₂ (M+H)⁺: m/z=225.1; Found: 225.1.

Step 2. 3-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)cyclobutanone

To a solution of 1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanone(530 mg, 2.4 mmol) in ether (10 mL) was added zinc-copper couple (1.8 g,14 mmol). The reaction mixture was heated at 40° C. and a solution oftrichloroacetyl chloride (1.4 mL, 13 mmol) and phosphoryl chloride (1.2mL, 13 mmol) in 1,2-dimethoxyethane (3 mL) was added slowly over 2 h.After addition, the reaction mixture was stirred under reflux overnight.The reaction was quenched with saturated NaHCO₃ solution and dilutedwith ether. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue and zinc (0.31 g, 4.7 mmol) inacetic acid (10 mL) was stirred at room temperature for 2 h and thenreflux overnight. Another portion of zinc was added and reflux foranother 4 h. The mixture was diluted with water and extracted withether. The organic phase was washed successively with a saturated NaHCO₃solution, water and brine, then dried over MgSO₄ and concentrated. Thecrude material was purified with flash chromatography (eluting with 0 to30% ethyl acetate in hexanes) to give the desired product (0.17 g, 27%).LCMS calculated for C₁₄H₁₆ClO₃ (M+H)⁺: m/z=267.1; Found: 267.0.

Step 3.3-[3-Chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]cyclobutanol

This compound was prepared according to the procedure of Example 13 step5, using of 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)cyclobutanoneand sodium tetrahydroborate as the starting materials. LCMS calculatedfor C₁₄H₁₉ClO₃Na (M+Na)⁺: m/z=293.1; Found: 293.1.

Step 4.3-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]cyclobutanol

To a solution of3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]cyclobutanol(170 mg, 0.628 mmol) in dimethyl sulfoxide (1 mL) was added cyanuricchloride (64 mg, 0.34 mmol). After stirred overnight, the reactionmixture was diluted with ether and water. The aqueous layer wasextracted with ethyl acetate once. The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude was purified with silica gel column to give the desired product(39.6 mg, 22%). LCMS calculated for C₁₄H₁₈ClO₂ (M-Cl)⁺: m/z=253.1;Found: 253.2.

Step 5.3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}cyclobutanoltrifluoroacetate

This compound was prepared according to the procedure of Example 139step 5, using of3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]cyclobutanol and3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as the starting materials.The product was isolated as a racemic mixture. LCMS calculated forC₂₀H₂₅ClN₅O₂ (M+H)⁺: m/z=402.2; Found: 402.2.

Example 167.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamidebis(2,2,2-trifluoroacetate)

Step 1. 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone

To a stirred solution of 1-(5-chloro-2-methoxy-4-methylphenyl)ethanone(5.00 g, 25.2 mmol, from Oakwood) in acetic acid (100 mL) was addedN-bromosuccinimide (4.93 g, 27.7 mmol) and the resulting mixture heatedat 100° C. for 18 hours. After cooling to ambient temperature, thereaction mixture was concentrated in vacuo, then neutralized with sat.sodium bicarbonate, filtered off insoluble succinimide. The filtrate wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over sodium sulfate, and then concentrated to dryness underreduced pressure. The residue was purified on silica gel, eluting with 0to 50% EtOAc in hexanes, to give the desired products (2.66 g, 38%).LCMS calculated for C₁₀H₁₁BrClO₂ (M+H)⁺: m/z=277.0; found: 277.0. ¹H NMR(DMSO-d₆, 300 MHz): δ 7.70 (1H, s), 3.77 (3H, s), 2.57 (3H, s), 2.50(3H, s) ppm.

Step 2. 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol

Sodium tetrahydroborate (0.31 g, 8.1 mmol) was added to a mixture of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.5 g, 5.4 mmol)in methanol (25 mL) at 0° C. and the resultant reaction mixture wasstirred at room temperature for 1 hour. The solvent was removed and theresulting residue was diluted with ethyl acetate, washed with sat.NaHCO₃, water, brine, then dried over Na₂SO₄, filtered and concentrated.The crude product was purified by silica gel chromatography, elutingwith 0 to 40% EtOAc in hexanes, to give the desired product (0.30 g,90%).

Step 3. 3-Bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene

A mixture of cyanuric chloride (1.7 g, 9.2 mmol) andN,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperaturefor 10 minutes and then a solution of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (from Example 16,Step 1) (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added andthe reaction was stirred at room temperature overnight. The mixture wasdiluted with methylene chloride, washed with sat. NaHCO₃, water, brine,dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by silica gel chromatography, eluting with 0 to 10% EtOAc inhexanes, to give the desired product (1.01 g, 60%).

Step 4.1-[1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (150 mg,0.503 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76mmol, ACES Pharma Product List, item #47024), potassium iodide (9.0 mg,0.05 mmol) and cesium carbonate (330 mg, 1.0 mmol) inN,N-dimethylformamide (4 mL) and was stirred at 140° C. for 1 h. Themixture was diluted with methylene chloride, washed with sat. NaHCO₃,water, brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by silica gel chromatography, eluting with 0 to 70%EtOAc in CH₂Cl₂, to give the desired product (103 mg, 50%). LCMScalculated for C₁₆H₁₈BrClN₅O (M+H)⁺: m/z=410.0; Found: 410.2. Theracemic products were applied on a Phenomenex Lux-Cellulose 1 column(21.1×250 mm, 5 micron particle size), eluting with 5% ethanol inhexanes at a flow rate of 18 mL/min, ˜13 mg/injection, to provide twoenantiomers. Peak 1, retention time: 12.35 min; Peak 2, retention time:14.98 min.

Step 5.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamidebis(2,2,2-trifluoroacetate)

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(25 mg, 0.061 mmol) (first peak from previous step chiral separation),N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(25 mg, 0.091 mmol, from PepTech Corp. Encyclopedia of Amino AcidAnalogs and Boronic Acids, item #BE1622-1), sodium carbonate (13 mg,0.12 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (9.9 mg, 0.012 mmol) inacetonitrile (0.8 mL)/water (0.3 mL) was degassed with N₂ and thenstirred at 95° C. for 2 h. After cooling to room temperature, themixture was filtered and the filtrate purified on RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.05%trifluoroacetic acid, at flow rate of 30 mL/min) to give the desiredproduct as bis-TFA salt (2.9 mg, 6.7%). The product was isolated as asingle enantiomer. LCMS calculated for C₂₄H₂₇ClN₇O₂ (M+H)⁺: m/z=480.2;Found: 480.2. ¹H NMR (500 MHz, DMSO-d₆) δ: 8.78 (2H, br s), 8.48 (1H,m), 8.36 (1H, s), 7.86 (1H, br s), 7.65 (1H, br s), 7.58 (1H, s), 6.33(1H, q, J=7.0 Hz), 3.19 (3H, s), 3.03 (3H, s), 2.97 (3H, s), 2.62 (3H,s), 2.06 (3H, s), 1.81 (3H, d, J=7.0 Hz) ppm.

Example 174.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-cyclopropyl-N-methylnicotinamidebis(2,2,2-trifluoroacetate)

Step 1.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}nicotinonitrile

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(first peak from Example 167, step 4 chiral separation, 106 mg, 0.25mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(70. mg, 0.31 mmol, from Combi-Blocks Catalog, item #PN-8893), sodiumcarbonate (43 mg, 0.41 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (1:1) (33 mg, 0.041 mmol) in acetonitrile (2mL)/water (0.6 mL) was degassed with N₂ and then stirred at 95° C. for 2h. The mixture was diluted with methylene chloride, washed with sat.NaHCO₃, water, brine, dried over Na₂SO₄, filtered and concentrated. Theproduct (95 mg, 87%) was purified by chromatography eluting withCH₂Cl₂/MeOH (max. MeOH 5%). LCMS calculated for C₂₂H₂₁ClN₇O (M+H)⁺:m/z=434.2; Found: 434.2.

Step 2.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)nicotinicacid dihydrochloride

4.0 M Sodium hydroxide in water (0.3 mL, 1 mmol) was added to a mixtureof5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}nicotinonitrile(0.090 g, 0.21 mmol) in ethanol (1.0 mL) and the mixture was then heatedat 95° C. for 6 h. At this time, conc. HCl was added to adjust PH to ˜3.The solvent was removed and the residue was used in the next stepwithout further purification LCMS calculated for C₂₂H₂₂ClN₆O₃ (M+H)⁺:m/z=453.1; Found: 453.2.

Step 3.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-cyclopropyl-N-methylnicotinamide

N-Methylcyclopropanamine hydrochloride (4.0 mg, 0.04 mmol) was added toa solution of5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)nicotinicacid dihydrochloride (9.6 mg, 0.021 mmol) and BOP (10 mg, 0.03 mmol) inDMF (0.7 mL) at room temperature followed by the addition oftriethylamine (13 μL, 0.10 mmol). The reaction was stirred for 1 h. Theproduct was purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.05% trifluoroacetic acid, atflow rate of 30 mL/min) to give the desired product as bis-TFA salt (2.6mg, 17%). The product was isolated as a single enantiomer. LCMScalculated for C₂₆H₂₉ClN₇O₂ (M+H)⁺: m/z=506.2; Found: 506.2.

Example 1793-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-methylpropanamide2,2,2-trifluoroacetate

Step 1. tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}propanoate

To a microwave vial was added1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(Peak 1 from Example 167, step 4 chiral separation, 35 mg, 0.085 mmol),potassium (3-tert-butoxy-3-oxopropyl)trifluoroborate (30. mg, 0.13 mmol,from Frontier Scientific, item #P10370), potassium phosphate (54 mg,0.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (9.8 mg, 0.0085mmol) and toluene (0.7 mL)/water (0.2 mL). The vial was sealed anddegassed with N₂ three times. The reaction was heated at 110° C. for 20h. The crude was filtered and the product (20 mg, 50%) was purified bychromatography eluting with CH₂Cl₂/MeOH (max. MeOH 6%). LCMS calculatedfor C₂₃H₃₁ClN₅O₃ (M+H)⁺: m/z=460.2; Found: 460.3.

Step 2.3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}propanoicacid trifluoroacetate

TFA (0.3 mL, 4 mmol) was added to a solution of tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}propanoate(35 mg, 0.076 mmol) in methylene chloride (0.2 mL) and the mixture wasstirred at room temperature for 2 h. The solvent was removed and theproduct was used in the next step without further purification. LCMScalculated for C₁₉H₂₃ClN₅O₃ (M+H)⁺: m/z=404.1; Found: 404.0.

Step 3.3-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-methylpropanamide2,2,2-trifluoroacetate

2.0 M Methylamine in THF (30 μL, 0.06 mmol) was added to a solution of3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}propanoicacid (8.9 mg, 0.022 mmol) and BOP (10 mg, 0.03 mmol) inN,N-dimethylformamide (0.7 mL) at room temperature followed by addingtriethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 h.The product was purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.05% trifluoroacetic acid, atflow rate of 30 mL/min) to give the desired product as TFA salt (3.2 mg,27%). The product was isolated as a single enantiomer. LCMS calculatedfor C₂₀H₂₆ClN₆O₂ (M+H)⁺: m/z=417.2; Found: 417.0.

Example 1811-(1-(5-Chloro-2-methoxy-4-methyl-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)phenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1. tert-Butyl4-(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(Peak 1 from Example 167, step 4 chiral separation, 42 mg, 0.1 mmol),tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(48 mg, 0.13 mmol, from Combi-Blocks Catalog, item #FM-2957), sodiumcarbonate (18 mg, 0.17 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (14 mg, 0.017 mmol) in acetonitrile (2mL)/water (0.4 mL) was degassed with N₂ and the stirred at 95° C. for 2h. The mixture was diluted with methylene chloride, washed with sat.NaHCO₃, water, brine, dried over Na₂SO₄, filtered and concentrated. Theproduct was purified by chromatography eluting with CH₂Cl₂/MeOH (max.MeOH 5%). LCMS calculated for C₂₉H₃₈ClN₈O₃ (M+H)⁺: m/z=581.2; Found:581.3.

Step 2.1-(1-(5-Chloro-2-methoxy-4-methyl-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

TFA (0.3 mL, 4 mmol) was added to a solution of tert-butyl4-(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate(30 mg, 0.052 mmol) in methylene chloride (0.2 mL) at room temperatureand the mixture was stirred for 1 h. The crude was purified usingRP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product. LCMS calculated for C₂₄H₃₀ClN₈O(M+H)⁺: m/z=481.2; Found: 481.1.

Step 3.1-(1-{5-Chloro-2-methoxy-4-methyl-3-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

12.0 M Formaldehyde in water (0.01 mL, 0.2 mmol) was added to a mixtureof1-{-1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(8.0 mg, 0.017 mmol) and N,N-diisopropylethylamine (0.012 mL, 0.066mmol) in methylene chloride (0.2 mL) at 0° C. The reaction mixture wasstirred for 10 min, at this time sodium triacetoxyborohydride (5.3 mg,0.025 mmol) was added and the reaction was stirred at 0° C. for 1 h. Thecrude was purified using RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 30 mL/min) to give the desired product (2.0 mg, 24%). Theproduct was isolated as a single enantiomer. LCMS calculated forC₂₅H₃₂ClN₈O (M+H)⁺: m/z=495.2; Found: 495.0.

Example 182.1-(1-{3-[1-(1-Acetylpiperidin-4-yl)-1H-pyrazol-4-yl]-5-chloro-2-methoxy-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Acetyl chloride (2.4 μL, 0.033 mmol) was added to a solution of1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(8.0 mg, 0.017 mmol, chiral intermediate from Example 181, Step 2) andN,N-diisopropylethylamine (14 μL, 0.083 mmol) in methylene chloride (0.3mL) at 0° C. and the reaction was stirred at room temperature for 15min. The crude was purified using RP-HPLC (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product (1.0mg, 7.8%). The product was isolated as a single enantiomer. LCMScalculated for C₂₆H₃₂ClN₈O₂ (M+H)⁺: m/z=523.2; Found: 523.2.

Example 183.1-[1-(5-Chloro-3-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1.1-(2-Chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.39 g, 2.0 mmol), 1-bromo-2-chloroethane (0.3 mL, 3 mmol) and cesiumcarbonate (1.3 g, 4.0 mmol) in acetonitrile (6 mL) was stirred at 75° C.for 5 h. The mixture was diluted with ethyl acetate, washed with sat.NaHCO₃, water, brine, dried over Na₂SO₄, filtered and concentrated andthe product (0.45 g, 88%) was purified by chromatography eluting withhexanes/EtOAc (max. EtOAc 30%). LCMS calculated for C₁₁H₁₉BClN₂O₂(M+H)⁺: m/z=257.1; Found: 257.0.

Step 2.N,N-Dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine

A mixture of1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.10 g, 0.39 mmol), sodium iodide (58 mg, 0.39 mmol) and 2.0 Mdimethylamine in THF (1.0 mL, 2.0 mmol) in N,N-dimethylformamide (0.5mL) was stirred at 80° C. overnight. The solvent was removed to providethe desired product which was used in the next step. LCMS calculated forC₁₃H₂₅BN₃O₂ (M+H)⁺: m/z=266.2; Found: 266.3.

Step 3.1-[1-(5-chloro-3-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(Peak 1 from Example 167, step 4, 10 mg, 0.024 mmol),N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-ethanamine(8.6 mg, 0.036 mmol), sodium carbonate (5.2 mg, 0.049 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (4.0 mg, 0.0049 mmol) in acetonitrile (0.5mL)/water (0.1 mL) was vacuumed and the refilled with N₂ and the stirredat 95° C. for 2 h. The crude was purified using RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give the desiredproduct (3.1 mg, 28%). The product was isolated as a single enantiomer.LCMS calculated for C₂₃H₃₀ClN₈O (M+H)⁺: m/z=469.2; Found: 469.2.

Example 184.2-[(5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridin-2-yl)amino]ethanol

Step 1.1-{-[5-Chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(Peak 1 from Example 167, step 4, 25.0 mg, 0.06 mmol),2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (20.mg, 0.088 mmol), sodium carbonate (12 mg, 0.12 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (9.5 mg, 0.012 mmol) in acetonitrile (1mL)/water (0.3 mL) was degassed with N₂ and the stirred at 95° C. for 2h. The mixture was diluted with methylene chloride, washed with sat.NaHCO₃, water, brine, dried over Na₂SO₄, filtered and concentrated. Theproduct was purified by chromatography eluting with CH₂Cl₂/MeOH (max.MeOH 5%). LCMS calculated for C₂₁H₂₁ClFN₆O (M+H)⁺: m/z=427; Found:427.2.

Step 2.2-[(5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridin-2-yl)amino]ethanol

A mixture of1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(10 mg, 0.023 mmol) and ethanolamine (0.10 mL) in 1-butanol (1 mL) wasstirred at 130° C. for 5 h. The crude was purified using RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to givethe desired product (1.6 mg, 15%). The product was isolated as a singleenantiomer. LCMS calculated for C₂₃H₂₇ClN₇O₂ (M+H)⁺: m/z=468.2; Found:468.2.

Example 188.2-(5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)pyridin-2-yloxy)ethanol

Sodium hydride (20 mg, 0.5 mmol) was added to 1,2-ethanediol (0.5 mL, 9mmol) and the mixture was stirred at room temperature for 10 min. Atthis time1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(10 mg, 0.023 mmol) was added and then the reaction was stirred at 110°C. overnight. The crude was purified using RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product (1.8mg, 17%). The product was isolated as a single enantiomer. LCMScalculated for C₂₃H₂₆ClN₆O₃ (M+H)⁺: m/z=469.2; Found: 469.1.

Example 189.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-(2,2-difluoroethoxy)-6-methylphenyl)-N,N-dimethylpicolinamidebis(2,2,2-trifluoroacetate)

Step 1.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-hydroxy-6-methylphenyl)-N,N-dimethylpicolinamide

1.0 M Boron tribromide in CH₂Cl₂ (250 μL, 0.25 mmol) was added to amixture of5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(Example 167, step 5, (first peak) 60 mg, 0.13 mmol) in methylenechloride (1.2 mL) at −78° C. and then the reaction was warmed to roomtemperature. At this time conc. HCl (0.1 mL) was added and the mixturewas stirred for 4 h. The reaction was quenched by the addition of sat.NaHCO₃. The mixture was then extracted with methylene chloride. Thecombined extracts were washed with brine, dried and concentrated to givethe desired crude product (40 mg, 68%) which was used in the next stepwithout further purification. LCMS calculated for C₂₃H₂₅ClN₇O₂ (M+H)⁺:m/z=466.2; Found: 466.2.

Step 2.5-[3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-(2,2-difluoroethoxy)-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Diisopropyl azodicarboxylate (13 μL, 0.064 mmol) was added to a mixtureof5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[34-d]pyrimidin-1-yl)ethyl]-5-chloro-2-hydroxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(15.0 mg, 0.0322 mmol), 2,2-difluoroethanol (7.9 mg, 0.096 mmol, fromAlfa Aesar, item #B22201) and triphenylphosphine (17 mg, 0.064 mmol) intetrahydrofuran (0.5 mL) at 0° C. and then the reaction was stirred atroom temperature for 24 h. The crude was purified on RP-HPLC (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to give thedesired product as bis-TFA salt (1.6 mg, 6.6%). The product was isolatedas a single enantiomer. LCMS calculated for C₂₅H₂₇ClF₂N₇O₂ (M+H)⁺:m/z=530.2; Found: 530.2.

Example 190.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-(cyclopropylmethoxy)-6-methylphenyl)-N,N-dimethylpicolinamidebis(2,2,2-trifluoroacetate)

Diisopropyl azodicarboxylate (13 μL, 0.064 mmol) was added to a mixtureof5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-hydroxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(15 mg, 0.032 mmol, chiral intermediate from Example 189, Step 1),cyclopropyl carbinol (7.0 mg, 0.096 mmol) and triphenylphosphine (17 mg,0.064 mmol) in tetrahydrofuran (0.5 mL) at 0° C. and then the reactionwas stirred at room temperature for 24 h. The crude was purified onRP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% trifluoroacetic acid, at flow rateof 30 mL/min) to give the desired product as bis-TFA salt (2.4 mg, 10%).The product was isolated as a single enantiomer. LCMS calculated forC₂₇H₃₁ClN₇O₂ (M+H)⁺: m/z=520.2; Found: 520.3.

Example 191.5-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

Step 1.1-[1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (0.60 g,2.0 mmol, from Example 167, Step 3),3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (590 mg, 2.2 mmol, fromAnaSpec), cesium carbonate (0.98 g, 3.0 mmol) and potassium iodide (30mg, 0.2 mmol) in N,N-dimethylformamide (8 mL) was stirred at 140° C. for1 h. The mixture was cooled down and then the solvent was completelyremoved. The residue was stirred with CH₂Cl₂ (30 mL) at room temperaturefor 20 min and then filtered. The filtrate was concentrated and theproduct (0.65 g, 63%) was purified by chromatography eluting withCH₂Cl₂/EtOAc (max. EtOAc 60%). LCMS calculated for C₁₅H₁₅BrClIN₅O(M+H)⁺: m/z=521.9; Found: 521.9.

Step 2.1-[1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(12 mg, 0.017 mmol) was added to a mixture of vinyl boronic acid MIDA(110 mg, 0.6 mmol, from Aldrich, item #704415),1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.30 g, 0.57 mmol) and sodium carbonate (0.14 g, 1.1 mmol) in1,4-dioxane (1 mL) and water (0.1 mL) and then the reaction was degassedwith N₂ 3 times. The reaction was stirred at 95° C. for 4 h. The mixturewas diluted with methylene chloride, washed with sat. NaHCO₃, water,brine, dried over Na₂SO₄, filtered and concentrated. The product waspurified by chromatography eluting with CH₂Cl₂/EtOAc (max. EtOAc 60%).LCMS calculated for C₁₇H₁₈BrClN₅O (M+H)⁺: m/z=422.0; Found: 422.2.

Step 3.1-{4-Amino-1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}ethane-1,2-diol

To a solution of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(100 mg, 0.236 mmol) in t-butyl alcohol (2 mL) was addedN-methylmorpholine N-oxide (30.5 mg, 0.260 mmol) and water (0.74 mL). Tothe solution was then added aqueous osmium tetraoxide (0.075 mL, 4%).After 3 hr, another equivalent of N-methylmorpholine N-oxide was added.The reaction was stirred at room temperature overnight. The solution wasdiluted with water, extracted with ethyl acetate, dried over MgSO₄ andconcentrated to give the product which was used directly in the nextstep. LCMS calculated for C₁₇H₂₀BrClN₅O₃ (M+H)⁺: m/z=456.0; Found:456.0.

Step 4.4-Amino-1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde

To a solution of1-{4-amino-1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}ethane-1,2-diol(0.10 g, 0.22 mmol) in tetrahydrofuran (1.6 mL)/water (1.0 mL) was addedacetic acid (0.0032 mL, 0.057 mmol) and sodium periodate (0.140 g, 0.657mmol) at 0° C. After stirring for 2 h, the reaction mixture was dilutedwith water, extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄ and concentrated to give thedesired crude product which was used directly in the next step. LCMScalculated for C₁₆H₁₆BrClN₅O₂ (M+H)⁺: m/z=424.0; Found: 423.9.

Step 5.5-{3-[1-(4-Amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

A mixture of4-amino-1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde(20 mg, 0.047 mmol), {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronicacid (23 mg, 0.12 mmol), sodium carbonate (10 mg, 0.094 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (7.7 mg, 0.0094 mmol) in acetonitrile (0.3mL)/ethanol (0.1 mL)/water (0.1 mL) was degassed with N₂ and thenstirred at 95° C. for 3 h. The mixture was diluted with methylenechloride, washed with sat. NaHCO₃, water, brine, dried over Na₂SO₄,filtered and concentrated. The product was purified by chromatographyeluting with CH₂Cl₂/MeOH (max. MeOH 6%). LCMS calculated forC₂₄H₂₅ClN₇O₃ (M+H)⁺: m/z=494.2; Found: 494.1.

Step 6.5-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

To a solution of5-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(0.015 g, 0.030 mmol) in methylene chloride (0.5 mL) cooled at 0° C. wasadded dropwise diethylaminosulfur trifluoride (0.020 mL, 0.15 mmol). Themixture was stirred at room temperature overnight. The crude waspurified using RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product (1.7 mg, 11%). The product wasisolated as a racemic mixture. LCMS calculated for C₂₄H₂₅ClF₂N₇O₂(M+H)⁺: m/z=516.2; Found: 516.2.

Example 192.1-[1-(5-Chloro-3-cyclopropyl-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a microwave vial was added1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(15 mg, 0.037 mmol, from peak 1 from Example 167, step 4), potassiumcyclopropyltrifluoroborate (8 mg, 0.06 mmol, from Frontier Scientific,item #C10298), potassium phosphate (23 mg, 0.11 mmol), andtetrakis(triphenylphosphine)palladium (4.2 mg, 0.0036 mmol) and thentoluene (0.3 mL)/water (0.1 mL). The vial was sealed and degassed withN₂ three times. The reaction was heat at 110° C. for 20 h. The crude waspurified using RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product (1.1 mg, 8%). The product wasisolated as a single enantiomer. LCMS calculated for C₁₉H₂₃ClN₅O (M+H)⁺:m/z=372.2; Found: 372.2.

Example 194.{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}acetonitrile

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(30 mg, 0.073 mmol) (Peak 1 from Example 167, step 4),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.018 g, 0.095mmol, from Combi-Blocks Catalog, item #PN-8875), potassium fluoride (13mg, 0.22 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (1:1) (12 mg, 0.015 mmol) in dimethyl sulfoxide(0.8 mL)/water (0.3 mL) was degassed with N₂ and then stirred at 130° C.for 16 h. The crude was purified using RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product (2.4mg, 9%). The product was isolated as a single enantiomer. LCMScalculated for C₁₈H₂₀ClN₆O (M+H)⁺: m/z=371.1; Found: 371.1.

Example 195.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpicolinamidebis(2,2,2-trifluoroacetate)

Step 1. 1-(3-Bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanone

Into a round bottom flask was placed1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (6.0 g, 23 mmol)in anhydrous DMF (22.8 mL). Potassium carbonate (6.3 g, 46 mmol) wasthen added followed by iodoethane (2.73 mL, 34.2 mmol). The resultingsuspension was stirred at 60° C. for 2 h. The mixture was poured into100 mL water and extracted with 200 mL of ethyl ether. The organiclayers were separated, combined and washed with water and saturated NaClsolution, dried over anhydrous sodium sulfate, filtered, andconcentrated to 6.0 g of tan oil. LCMS calculated for C₁₁H₁₃BrClO₂(M+H)⁺: m/z=293.0; Found: 293.0.

Step 2. 1-(3-Bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanol

Sodium tetrahydroborate (0.31 g, 8.1 mmol) was added to a mixture of1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanone (1.5 g, 5.4 mmol)in methanol (25 mL) at 0° C. and the resultant reaction mixture wasstirred at room temperature for 1 hour. The solvent was removed and theresulting residue was diluted with ethyl acetate, washed with sat.NaHCO₃, water, brine, then dried over Na₂SO₄, filtered and concentrated.The crude product was purified by silica gel chromatography, elutingwith 0 to 30% EtOAc in hexanes (0.30 g, 90%).

Step 3. 3-Bromo-1-chloro-5-(1-chloroethyl)-4-ethoxy-2-methylbenzene

A mixture of cyanuric chloride (1.7 g, 9.2 mmol) andN,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperaturefor 10 minutes and then a solution of1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanol (1.72 g, 6.15 mmol)in methylene chloride (34 mL) was added and the reaction was stirred atroom temperature overnight. The mixture was diluted with methylenechloride, washed with sat. NaHCO₃, water, brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by silica gelchromatography, eluting with 0 to 10% EtOAc in hexanes (1.01 g, 60%).

Step 4.1-(1-(3-Bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-ethoxy-2-methylbenzene(150 mg, 0.50 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110mg, 0.76 mmol), potassium iodide (9 mg, 0.05 mmol) and cesium carbonate(330 mg, 1.0 mmol) in N,N-dimethylformamide (4 mL) was stirred at 140°C. for 1 h. The mixture was diluted with methylene chloride, washed withsat. NaHCO₃, water, brine, dried over Na₂SO₄, filtered and concentrated.The crude product was purified by silica gel chromatography, elutingwith 0 to 70% EtOAc in CH₂Cl₂ (103 mg, 50%). LCMS calculated forC₁₇H₂₀BrClN₅O (M+H)⁺: m/z=423.1; Found: 423.0. The racemic products wereapplied on a Phenomenex Lux-Cellulose 1 column (21.1×250 mm, 5 micronparticle size), eluting with 4% ethanol in hexanes at a flow rate of 18mL/min, ˜13 mg/injection, to provide two enantiomers. Peak 1, retentiontime: 8.64 min; Peak 2, retention time: 10.64 min.

Step 5.5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpicolinamidebis(2,2,2-trifluoroacetate)

A mixture of1-[1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(25 mg, 0.061 mmol) (first peak from previous step chiral separation),N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(25 mg, 0.09 mmol), sodium carbonate (13 mg, 0.12 mmol) and[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complexwith dichloromethane (1:1) (9.9 mg, 0.012 mmol) in acetonitrile (0.8mL)/water (0.3 mL) was degassed with N₂ and then stirred at 95° C. for 2hours. After cooling to room temperature, the mixture was filtered andthe filtrate purified on RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.05% trifluoroacetic acid, atflow rate of 30 mL/min) to give the desired product as bis-TFA salt (2.3mg, 5%). The product was isolated as a single enantiomer. LCMScalculated for C₂₅H₂₉ClN₇O₂ (M+H)⁺: m/z=494.2; Found: 494.2.

Example 200.4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamidebis(2,2,2-trifluoroacetate)

Step 1.4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile

A mixture of1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(peak 1 from Example 167, step 4, 322 mg, 0.76 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile(210 mg, 0.91 mmol, from Combi-Blocks Catalog, item #PN-0143), sodiumcarbonate (130 mg, 1.2 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (1:1) (99 mg, 0.12 mmol) in acetonitrile (5mL)/water (2 mL) was degassed with N₂ and the reaction was stirred at95° C. for 2 h. The mixture was diluted with methylene chloride, washedwith sat. NaHCO₃, water, brine, dried over Na₂SO₄, filtered andconcentrated. The product (0.28 g, 85%) was purified by chromatographyeluting with CH₂Cl₂/MeOH (max. MeOH 6%). LCMS calculated for C₂₂H₂₁ClN₇O(M+H)⁺: m/z=434.1; Found: 434.1.

Step 2.4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)picolinicacid dihydrochloride

1.0 M Sodium hydroxide (2.9 mL, 2.9 mmol) was added to a mixture of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile(0.250 g, 0.576 mmol) in ethanol (4.0 mL) and the resulting mixture washeated at 95° C. for 6 h. At this time, conc. HCl was added to adjustthe pH to ˜3. The solvent was removed and the residue was used in thenext step without further purification. LCMS calculated for C₂₂H₂₂ClN₆O₃(M+H)⁺: m/z=453.1; Found: 453.2.

Step 3.4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamidebis(2,2,2-trifluoroacetate)

2.0 M Dimethylamine in THF (2.0 mL, 4.0 mmol) was added to a solution of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylicacid (250 mg, 0.552 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(370 mg, 0.83 mmol) in N,N-dimethylformamide (4 mL) at 0° C. followed byadding triethylamine (0.23 mL, 1.6 mmol). The reaction was stirred for 1h. The crude mixture was purified on RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.05%trifluoroacetic acid, at flow rate of 30 mL/min) to give the desiredproduct as bis-TFA salt. The product was isolated as a singleenantiomer. LCMS calculated for C₂₄H₂₇ClN₇O₂ (M+H)⁺: m/z=480.2; Found:480.2. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.67 (br s, 1H), 8.36 (s, 1H), 7.58(s, 1H), 7.41 (m, 2H), 6.32 (q, 2H), 3.20 (s, 3H), 3.00 (s, 3H), 2.94(s, 3H), 2.62 (s, 3H), 2.03 (s, 3H), 1.80 (d, 3H) ppm.

Example 203.2-(4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-1H-pyrazol-1-yl)acetamide

Step 1. tert-Butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate

1.0 M Potassium tert-butoxide in THF (2.4 mL, 2.4 mmol) was added to asolution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.39 g, 2.0 mmol) in N,N-dimethylformamide (6.0 mL) at 0° C. Thereaction mixture was stirred at room temperature for 5 min. After cooledto 0° C., to the mixture was added t-butyl bromoacetate (0.5 mL, 3mmol). The reaction was stirred at room temperature for 2 h, thendiluted with ethyl acetate, washed with sat. NaHCO₃, water, brine, driedover Na₂SO₄, filtered and concentrated. The product (0.5 g, 81%) waspurified by chromatography eluting with hexanes/EtOAc (max. EtOAc 30%).LCMS calculated for C₁₅H₂₆BN₂O₄ (M+H)⁺: m/z=309.2; Found: 309.1.

Step 2. tert-Butyl(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)acetate

A mixture of1-[1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(70 mg, 0.16 mmol) (first peak from Example 195, step 4), tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate(65 mg, 0.21 mmol), sodium carbonate (30. mg, 0.28 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (23 mg, 0.028 mmol) in acetonitrile (3mL)/water (0.7 mL) was degassed with N₂ and then stirred at 95° C. for 2h. The mixture was diluted with methylene chloride, washed with sat.NaHCO₃, water, brine, dried over Na₂SO₄, filtered and concentrated. Theproduct (65 mg, 78%) was purified by chromatography eluting withCH₂Cl₂/MeOH (max. MeOH 5%). LCMS calculated for C₂₆H₃₃ClN₇O₃ (M+H)⁺:m/z=526.2; Found: 526.3.

Step 3.(4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)aceticacid bis trifluoroacetate

Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)acetate(0.065 g, 0.12 mmol) in methylene chloride (0.5 mL). The reaction wasstirred at room temperature for 4 h. The solvent was removed to providethe crude product which was used in the next step. LCMS calculated forC₂₂H₂₅ClN₇O₃ (M+H)⁺: m/z=470.2; Found: 470.1.

Step 4.2-(4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)acetamide

Ammonium carbonate (20 mg, 0.21 mmol) was added to a solution of(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)aceticacid bis trifluoroacetate (10 mg, 0.021 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperaturefollowed by triethylamine (8.8 μL, 0.064 mmol). The reaction was stirredfor 1 h. The crude was purified using RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product (2.5mg, 25%). The product was isolated as a single enantiomer. LCMScalculated for C₂₂H₂₆ClN₅O₂ (M+H)⁺: m/z=469.2; Found: 469.2.

Example 208.6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylnicotinamidebis(trifluoroacetate)

Step 1.1-{1-[5-Chloro-2-ethoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1-[1-(3-Bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.050 g, 0.12 mmol, Peak 1 from Example 195, step 4) was combined in amicrowave vial with potassium acetate (0.035 g, 0.35 mmol) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](0.060 g,0.24 mmol) in dimethyl sulfoxide (0.44 mL) at room temperature. This wasdegassed with nitrogen and then[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (1:1) (0.01 g, 0.01 mmol) was added. The reactionwas heated in an oil bath to 105° C. overnight. This was allowed tocool, then taken up in ethyl acetate and washed with water, brine, driedover magnesium sulfate and concentrated. The product (15 mg, 20%) waspurified by chromatography eluting with CH₂Cl₂/MeOH (max. MeOH 10%).LCMS calculated for C₂₃H₃₂BClN₅O₃ (M+H)⁺: m/z=472.2; Found: 472.3.

Step 2.6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylnicotinamidebis(trifluoroacetate)

A mixture of1-{1-[5-chloro-2-ethoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(15 mg, 0.032 mmol), 6-chloro-N,N-dimethylnicotinamide (12 mg, 0.064mmol), sodium carbonate (9.0 mg, 0.085 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (1:1) (6.9 mg, 0.0085 mmol) in acetonitrile (0.9mL)/water (0.2 mL) was degassed with N₂ and then stirred at 95° C.overnight. The crude was purified using RP-HPLC (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.05%trifluoroacetic acid, at flow rate of 30 mL/min) to give the desiredproduct as TFA salt (2 mg, 9%). The product was isolated as a singleenantiomer. LCMS calculated for C₂₅H₂₉ClN₇O₂ (M+H)⁺: m/z=494.2; Found:494.2.

Example 209.5-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-methoxy-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzonitrile

Pre-formed catalyst (0.05 mL, from Example 40) was added to a mixture1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(7.7 mg, 0.019 mmol), zinc (0.54 mg, 0.0082 mmol) and zinc cyanide (2.2mg, 0.019 mmol) in N,N-dimethylacetamide (0.3 mL). The mixture wasdegassed with nitrogen 3 times. The reaction was heated at 120° C. for1.5 h. The crude was purified using RP-HPLC (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product (2.1mg, 27%). The product was isolated as a single enantiomer. LCMScalculated for C₂₁H₂₃N₈O (M+H)⁺: m/z=403.2; Found: 403.2.

Example 211.3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylbenzonitrile

N,N,N′,N′-Tetramethylethylenediamine (10 μL, 0.07 mmol), zinc cyanide (3mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.9 mg, 0.001mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2mg, 0.003 mmol) was added successively to a solution of1-[1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(14 mg, 0.033 mmol, Peak 1 from Example 195, step 4) inN,N-dimethylformamide (0.5 mL) in a microwave tube. The tube was sealedand degassed and refilled with N₂ three times, and then heated at 160°C. under microwave irradiation for 400 seconds. The mixture was cooled,filtered and the crude filtrate was purified using RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 30 mL/min) to give the desiredproduct (2.4 mg, 20%). The product was isolated as a single enantiomer.LCMS calculated for C₁₈H₂₀ClN₆O (M+H)⁺: m/z=371.1; Found: 371.2.

Experimental procedures for the compounds of Examples 69, 70, 75, 78,97, 98, 100, 103, 106, 107, 109, 111, 112, 114, 116, 119, 120, 122-124,132, 135, 142-148, 151, 153-155, 157, 160, 162, 168-173, 175-178, 180,185-187, 193, 196-199, 201, 202, 204-207, and 210 are summarized inTables 1 and 2.

TABLE 1

Ex. No. Name R² R⁴ R⁵ R³ Salt Proc.¹ 69 (2R)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d] pyrimidin-1-yl)ethyl]-5- cyloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl) propan-2-ol² Me F Cl

 68 70 1-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5- chloro-6-fluoro-2- methoxyphenyl}azetidin-1-yl)-2-methylpropan-2-ol² Me F Cl

 68 97 (2R)-1-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5- chloro-2-ethoxy-6- methylphenyl}azetidin-1-yl)propan-2-ol² Et Me Cl

22 TFA  96 98 1-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5- chloro-2-ethoxy-6- methylphenyl}azetidin-1-yl)-2-methylpropan-2-ol³ Et Me Cl

2 TFA  96 100 (2R)-1-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5- chloro-2-ethoxy-6- methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol² Et Me Cl

TFA  99 103 (2R)-1-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5- chloro-2-methoxy-6- methylphenyl}azetidin-1-yl)propan-2-ol⁵ Me Me Cl

102 106 2-(3-{3-[1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy- 6-methylphenyl}azetidin-1-yl)propanenitrile⁴ Me Me Cl

105 107 1-(1-{5-Chloro-2-methoxy-4- methyl-3-[1-(tetrahydrofuran-3-yl)azetidin-3-yl]phenyl}ethyl)- 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine⁴ Me Me Cl

 1 109 3-(3-{3-[1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy- 6-methylphenyl}azetidin-1-yl)-1,1,1-trifluoropropan-2-ol⁴ Me Me Cl

102 111 2-(3-{3-[1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy- 6-methylphenyl}azetidin-1-yl) acetamide³Me Me Cl

105 112 1-(1-{5-Chloro-3-[1-(2,2- difluoroethyl)azetidin-3-yl]-2-methoxy-4-methylphenyl} ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine³ Me Me Cl

105 114 1-(1-{5-Chloro-3-[1-(2-fluoro- 1-methylethyl)azetidin-3-yl]-2-methoxy-4-methylphenyl} ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine⁴ Me Me Cl

 1 116 (2S)-3-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro- 2-methoxy-6-methylphenyl}azetidin-1-yl)-1,1,1- trifluoropropan-2-ol⁵ Me Me Cl

115 119 1-(1-{5-Chloro-3-[1- (cyclopropylcarbonyl)azetidin-3-yl]-2-methoxy-4- methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-amine³ Me Me Cl

TFA 117 120 1-[1-(5-Chloro-2-methoxy-4- methyl-3-{1-[(5-methylisoxazol-4-yl)carbonyl]azetidin-3-yl} phenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4- amine³ Me Me Cl

TFA 117 122 1-[(3-{3-[1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy- 6-methylphenyl}azetidin-1-yl)carbonyl]cyclopropanol³ Me Me Cl

TFA 121 123 1-(3-{3-[1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy- 6-methylphenyl}azetidin-1-yl)-2-methyl-1-oxopropan-2-ol³ Me Me Cl

TFA 121 124 1-(1-{5-Chloro-2-methoxy-4- methyl-3-[1-(1H-pyrazol-4-ylcarbonyl)azetidin-3-yl]phenyl} ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine³ Me Me Cl

TFA 121 142 (2R)-1-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro- 2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol⁴ Et F Cl

140 143 (2S)-1-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro- 2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol⁴ Et F Cl

140 144 2-(3-{3-[1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6- fluorophenyl}azetidin-1-yl) ethanol² EtF Cl

139 145 1-{1-[5-Chloro-2-ethoxy-4- fluoro-3-(1-methylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- amine² Et F Cl

139 146 1-{1-[5-Chloro-2-ethoxy-3-(1- ethylazetidin-3-yl)-4-fluorophenyl]ethyl}-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4- amine² Et FCl

139 147 1-(1-{5-Chloro-3-[1-(2,2- difluoroethyl)azetidin-3-yl]-2-ethoxy-4-fluorophenyl}ethyl)-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine² Et F Cl

141 148 2-(3-{3-[1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6- fluorophenyl}azetidin-1-yl) acetamide²Et F Cl

141 157 (2S)-2-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro- 2-methoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol⁵ Me Me Cl

156 160 (2S)-2-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro- 2-methoxy-6-methylphenyl}azetidin-1-yl)-N,N- dimethylpropanamide⁵ Me Me Cl

159 162 3-(3-{3-[1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy- 6-methylphenyl}azetidin-1-yl)-2-methylpropanenitrile⁴ Me Me Cl

161 168 1-(1-(5-chloro-2-methoxy-4- methyl-3-(pyrimidin-5-yl)phenyl)ethyl)-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- amine³ Me Me Cl

2TFA 167 169 1-(1-(3-(2-aminopyrimidin-5- yl)-5-chloro-2-methoxy-4-methylphenyl)ethyl)-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4- amine³ MeMe Cl

167 170 5-(3-(1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6- methylphenyl)nicotinonitrile³ Me Me Cl

2TFA 167 171 1-(1-(3-(6-aminopyridin-3-yl)- 5-chloro-2-methoxy-4-methylphenyl)ethyl)-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin- 4-amine³ MeMe Cl

167 172 1-(1-(5-chloro-2-methoxy-4- methyl-3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)ethyl)-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine³ Me Me Cl

167 173 5-(3-(1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6- methylphenyl)-N- methylpicolinamide³ Me MeCl

167 175 5-{3-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6- methylphenyl}-N- methylnicotinamide³ Me MeCl

2TFA 174 176 1-[(5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridin-3-yl) carbonyl]piperidin-4-ol³ Me Me Cl

2TFA 174 177 1-[(5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridin-3-yl) carbonyl]azetidine-3- carbonitrile³ Me Me Cl

2TFA 174 178 5-(3-(1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6- methylphenyl)-N- (2-aminoethyl)-N-methylnicotinamide³ Me Me Cl

3TFA 174 180 3-(3-(1-(4-Amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6- methylphenyl)-N,N- dimethylpropanamide³Me Me Cl

TFA 179 185 1-(1-(5-chloro-3-(6- (dimethylamino)pyridin-3-yl)-2-methoxy-4-methylphenyl)ethyl)- 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine³ Me Me Cl

2TFA 184 186 1-(1-(5-chloro-3-(2- (dimethylamino)pyridin-4-yl)-2-methoxy-4-methylphenyl)ethyl)- 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine³ Me Me Cl

184 187 1-(4-(3-(1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6- methylphenyl)pyridin-2-yl)azetidin-3-ol³ Me Me Cl

184 193 1-{1-[5-Chloro-3- (cyclopropylmethyl)-2-methoxy-4-methylphenyl]ethyl}-3- methyl-1H-pyrazolo[3,4-d] pyrimidin-4-amine³ MeMe Cl

192 196 5-(3-(1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6- methylphenyl)-N,N- dimethylnicotinamide³ EtMe Cl

195 197 1-(1-(5-chloro-2-ethoxy-4- methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- amine³ Et MeCl

195 198 1-(1-(5-chloro-2-ethoxy-4- 3-(5-methylsulfonyl)pyridin-3-yl)phenyl)ethyl)-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- amine³ Et MeCl

195 199 5-(3-(1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6- methylphenyl)-N- methylpicolinamide³ Et MeCl

195 201 4-(3-(1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6- methylphenyl)-N,N- dimethylnicotinamide³ EtMe Cl

200 202 4-(3-(1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6- methylphenyl)-N-(2- hydroxyethyl)-N-methylpicolinamide³ Et Me Cl

200 204 2-(4-(3-(1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6- methylphenyl)-1H-pyrazol-1-yl)-N-methylacetamide³ Et Me Cl

203 205 2-(4-(3-(1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6- methylphenyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide³ Et Me Cl

203 206 2-(4-(3-(1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6- methylphenyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide³ Me Me Cl

203 207 2-(4-(3-(1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6- methylphenyl)-1H-pyrazol-1-yl)-N,N-dimethylpropanamide⁴ Me Me Cl

203 210 5-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-ethoxy-2-methyl-3-(1- methyl-1H-pyrazol-4-yl) benzonitrile³ EtMe CN

209 ¹Synthesized according to the experimental procedure of compoundlisted; ²Compound isolated as a racemic mixture; ³Compound isolated as asingle enantiomer ⁴Compound isolated as a mixture of diastereomers;⁵Compound isolated as a single diastereomer.

TABLE 2

Ex. No. Name R² R⁴ R⁵ R³ Salt Proc.¹ 75 1-{1-[5-Chloro-4-fluoro-2-methoxy-3-(1-methylazetidin-3- yl)phenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine² Me F Cl

 73 78 5-{1-[4-Amino-3-(difluoromethyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-2-fluoro-3-[1-(2- hydroxyethyl)azetidin-3-yl]-4-methoxybenzonitrile² Me F CN

 77 132 5-{1-[4-Amino-3-(difluoromethyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-{1-[(2R)-2- hydroxypropyl]azetidin-3-yl}-4-methoxy-2-methylbenzonitrile⁴ Me Me CN

131 135 (2R)-2-[3-(3-{1-[4-Amino-3- (difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2- methoxy-6-methylphenyl)azetidin-1-yl]-N-methylpropanamide⁴ Me Me CN

134 151 1-{1-[5-Chloro-2-ethoxy-4-fluoro- 3-(1-methylazetidin-3-yl)phenyl]ethyl}-3- (difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine² Et F Cl

150 153 1-[3-(3-{1-[4-Amino-3- (difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2- ethoxy-6-fluorophenyl)azetidin-1-yl]-2-methylpropan-2-ol² Et F Cl

140 154 (2S)-1-[3-(3-{1-[4-Amino-3- (difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2- ethoxy-6-fluorophenyl)azetidin-1-yl]propan-2-ol⁴ Et F Cl

140 155 (2R)-1-[3-(3-{1-[4-Amino-3- (difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2- ethoxy-6-fluorophenyl)azetidin-1-yl]propan-2-ol⁴ Et F Cl

140 ¹Synthesized according to the experimental procedure of compoundlisted; ²Compound isolated as a racemic mixture; ⁴Compound isolated as amixture of diastereomers.Analytical Data

¹H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer,or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data(MS) for the compounds of Examples 69, 70, 75, 78, 97, 98, 100, 102-138,142-148, 151, 153-155, 157, 160, 162, 168-173, 175-178, 180, 185-187,193, 196-199, 201, 202, 204-207, and 210 is provided below in Table 3.

TABLE 3 Ex. MS No. [M + H]⁺ Solvent MHz ¹H NMR Spectra 69 449.1 — — — 70463.2 — — — 75 441.1 — — — 78 462.2 — — — 97 459.1 — — — 98 473.2 — — —100 473.1 — — — 102 445.2 — — — 103 445.3 CDCl₃ 300 δ 8.29 (s, 1H), 7.41(s, 1H), 6.37 (q, J = 7.0 Hz, 1H), 5.40 (s, 2H) 4.18-3.66 (m, 4H), 3.58(s, 3H), 3.27-3.02 (m, 2H), 2.65 (s, 3H), 2.53-2.21 (m, 2H), 2.11 (s,3H), 1.93-1.60 (m, 4H), 1.12 (d, J = 6.2 Hz, 3H). 104 431.3 — — — 105426.0 CDCl₃ 400 δ 8.28 (s, 1H), 7.44 (s, 1H), 6.36 (q, J = 7.1 Hz, 1H),5.46 (s, 2H) 4.05-3.78 (m, 3H), 3.59 (s, 3H), 3.53-3.38 (m, 3H), 3.25(dd, J = 8.6, 6.0 Hz, 1H), 2.65 (s, 3H), 2.12 (s, 3H), 1.83 (d, J = 7.1Hz, 3H). 106 440.2 CDCl₃ 400 δ 8.29 (s, 1H), 7.44 (s, 1H), 6.37 (q, J =6.9 Hz, 1H), 5.40 (s, 2H), 4.08-3.76 (m, 3H), 3.67-3.47 (m, 4H), 3.40(q, J = 6.6 Hz, 1H), 3.20 (dd, J = 8.0, 4.2 Hz, 1H), 2.65 (s, 3H), 2.13(d, J = 4.1 Hz, 3H), 1.83 (dd, J = 7.1, 1.1 Hz, 3H), 1.35 (dd, J = 7.1,2.1 Hz, 3H). 107 457.1 CDCl₃ 300 δ 8.29 (s, 1H), 7.41 (s, 1H), 6.37 (q,J = 7.0 Hz, 1H), 5.42 (s, 2H) 4.13-3.70 (m, 6H), 3.70-3.43 (m, 6H),3.20-2.99 (m, 1H), 2.99-2.77 (m, 2H), 2.65 (s, 3H), 2.12 (d, J = 1.9 Hz,3H), 1.83 (d, J = 7.1 Hz, 3H). 108 469.1 CDCl₃ 300 δ 8.28 (d, J = 1.6Hz, 1H), 7.41 (s, 1H), 6.37 (q, J = 7.1 Hz, 1H), 5.42 (s, 2H), 4.15 (q,J = 8.2, 6.9 Hz, 2H), 4.05-3.88 (m, 1H), 3.58 (s, 3H), 3.40-3.27 (m,1H), 3.15 (dd, J = 9.3, 6.5 Hz, 1H), 2.95 (q, J = 9.5 Hz, 2H), 2.65 (s,3H), 2.10 (s, 3H), 1.84 (dd, J = 7.0, 3.4 Hz, 3H). 109 440.2 CDCl₃ 400 δ8.28 (s, 1H), 7.42 (s, 1H), 6.37 (q, J = 7.1 Hz, 1H), 5.56 (s, 2H),4.17-3.99 (m, 2H), 3.98-3.79 (m, 2H), 3.58 (d, J = 5.9 Hz, 3H),3.39-3.24 (m, 1H), 3.24-3.11 (m, 1H), 2.74 (dd, J = 12.7, 7.9 Hz, 1H),2.65 (s, 5H), 2.10 (s, 3H), 1.83 (d, J = 7.1 Hz, 3H). 110 472.2 — — —111 444.1 — — — 112 454.1 — — — 113 499.1 CDCl₃ 300 δ 8.29 (s, 1H), 7.42(d, J = 2.1 Hz, 1H), 6.37 (q, J = 7.1 Hz, 1H), 5.48 (s, 2H), 4.07 (m,3H), 3.98-3.77 (m, 2H), 3.58 (d, J = 3.6 Hz, 3H), 3.45-3.26 (m, 1H),3.25-3.08 (m, 1H), 2.85-2.53 (m, 5H), 2.11 (s, 3H), 1.83 (d, J = 7.1 Hz,3H). 114 447.2 CDCl₃ 300 δ 8.28 (s, 1H), 7.40 (s, 1H), 6.37 (q, J = 7.1Hz, 1H), 5.49 (s, 2H), 4.35 (dd, J = 5.2, 2.3 Hz, 1H), 4.19 (dd, J =4.9, 2.8 Hz, 1H), 4.12-3.95 (m, 2H), 3.88 (dt, J = 15.5, 7.9 Hz, 1H),3.58 (d, J = 6.5 Hz, 2H), 3.28-3.10 (m, 1H), 3.10-2.93 (m, 1H),2.75-2.54 (m, 3H), 2.20-2.01 (m, 3H), 1.94-1.69 (m, 5H), 0.97 (d, J =5.7 Hz, 3H). 115 499.1 CDCl₃ 400 δ 8.28 (s, 1H), 7.42 (s, 1H), 6.37 (q,J = 7.0 Hz, 1H), 5.53 (s, 2H), 4.19-4.00 (m, 2H), 3.90 (dd, J = 9.7, 5.4Hz, 2H) 3.59 (s, 3H), 3.44-3.34 (m, 1H), 3.13 (dd, J = 9.3, 6.7 Hz, 1H),2.74 (dd, J = 12.8, 7.7 Hz, 1H), 2.65 (s, 4H), 2.10 (s, 3H), 1.83 (d, J= 7.1 Hz, 3H). 116 454.1 DMSO- 400 δ 8.04 (s, 1H), 7.18 (s, 1H), 6.13(dt, J = 19.6, 6.8 Hz, d₆ 1H), 3.97-3.71 (m, 3H), 3.46 (s, 3H), 3.28 (s,1H), 2.91 (dt, J = 29.4, 7.6 Hz, 1H), 2.43 (m, 6H), 2.36 (dd, J = 12.3,8.0 Hz, 1H), 2.00 (s, 3H), 1.63 (d, J = 7.1 Hz, 3H). 117 495.2 DMSO- 400δ 8.13 (d, J = 18.4 Hz, 2H), 7.75 (s, 1H), 7.29 (s, 1H), d₆ 6.22 (q J =7.1 Hz, 1H), 4.41 (s, 1H), 3.86 (s, 2H), 3.61 (d, J = 4.9 Hz, 2H), 3.33(s, 6H), 2.55 (s, 3H), 2.23 (s, 3H), 1.71 (d, J = 7.0 Hz, 3H). 118 459.2— — — 119 455.1 — — — 120 496.1 — — — 121 459.2 — — — 122 471.0 — — —123 473.0 — — — 124 481.0 — — — 125 492.1 — — — 126 478.1 — — — 127465.2 CDCl₃ 300 δ 8.40 (s, 1H), 7.36 (s, 1H), 6.48 (q, J = 7.2 Hz, 1H),5.81 (s, 2H), 4.16-3.95 (m, 2H), 3.94-3.75 (m, 1H), 3.56 (s, 3H),3.18-3.02 (m, 1H), 3.00-2.83 (m, 1H), 2.31-2.18 (m, 1H), 2.14 (s, 3H),1.84 (d, J = 7.1 Hz, 4H), 0.97 (dd, J = 6.2, 3.1 Hz, 6H). 128 456.2 — —— 129 496.1 — — — 130 458.2 CDCl₃ 300 δ 8.39 (s, 1H), 7.63 (s, 1H), 6.49(q, J = 7.1 Hz, 1H), 5.85 (s, 2H), 4.16-3.97 (m, 2H), 3.87 (m, 1H), 3.56(t, J = 5.2 Hz, 2H), 3.14 (dd, J = 9.5, 6.9 Hz, 1H), 2.97 (dd, J = 9.3,6.4 Hz, 1H), 2.61-2.49 (m, 2H), 2.31 (s, 3H), 1.84 (d, J = 7.1 Hz, 3H),1.69 (br s, 1H), 1.48-1.34 (m, 2H), 0.97 (t, J = 7.3 Hz, 2H). 131 472.2— — δ 8.39 (s, 1H), 7.63 (d, J = 3.4 Hz, 1H), 6.49 (d, J = 7.1 Hz, 1H),5.79 (s, 2H), 4.15-3.96 (m, 2H), 3.88 (m, 1H), 3.70 (m, 1H), 3.63 (d, J= 2.0 Hz, 3H), 3.29-2.89 (m, 2H), 2.49-2.34 (m, 1H), 2.31 (s, 4H), 1.85(d, J = 7.1 Hz, 3H), 1.25 (s, 2H), 1.12 (d, J = 6.2 Hz, 3H). 132 472.2 —— — 133 486.2 CDCl₃ 300 δ 8.39 (s, 1H), 7.63 (s, 1H), 6.49 (q, J = 6.9Hz, 1H), 5.84 (s, 2H), 4.10 (q, J = 7.4 Hz, 2H), 3.92 (m, 2H), 3.62 (s,3H), 3.37-3.21 (m, 1H), 3.20-3.04 (m, 1H), 2.37 (s, 2H), 2.31 (s, 3H),1.85 (d, J = 7.1 Hz, 3H), 1.70 (br s, 1H), 1.15 (s, 6H). 134 499.1 — — —135 499.1 CDCl₃ 400 δ 8.38 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 6.8 Hz,1H), 6.79 (d, J = 3.1 Hz, 1H), 6.54-6.38 (m, 1H), 5.83 (s, 2H),4.04-3.86 (m, 2H), 3.86-3.70 (m, 1H), 3.64 (d, J = 11.0 Hz, 3H),3.27-2.87 (m, 2H), 2.84 (dd, J = 4.9, 3.8 Hz, 3H), 2.81-2.70 (m, 1H),2.31 (d, J = 8.1 Hz, 3H), 1.84 (dd, J = 7.1, 3.8 Hz, 4H), 1.17 (dd, J =6.8, 5.8 Hz, 3H). 136 478.1 — — — 137 472.2 — — — 138 456.2 CDCl₃ 400 δ8.39 (s, 1H), 7.70 (s, 1H), 6.49 (d, J = 6.2 Hz, 1H), 5.83 (s, 2H)4.63-4.38 (m, 2H), 4.37-4.03 (m, 2H), 3.74 (d, J = 21.2 Hz, 3H), 2.43(d, J = 4.6 Hz, 3H), 1.91 (d, J = 3.6 Hz, 4H), 1.85 (d, J = 7.0 Hz, 4H).142 463.1 — — — 143 463.2 — — — 144 449.1 — — — 145 419.1 DMSO- 300 δ8.10 (s, 1 H), 7.44 (d 1 H), 7.28 (bs, 2 H), 6.20 (m, 1 d₆ H), 3.77 (m,5 H), 2.95 (m, 2 H), 2.53 (s, 3 H), 2.17 (s, 3 H), 1.67 (d, 3 H), 1.30(t, 3 H) ppm. 146 433.1 DMSO- 300 δ 8.10 (s, 1 H), 7.44 (d 1 H), 7.31(bs, 2 H), 6.21 (m, 1 d₆ H) 3.80-3.63 (m, 5 H), 2.85 (m, 2 H), 2.49 (s,3 H), 2.33 (m, 2 H), 1.67 (d, 3 H), 1.31 (t, 3 H), 0.85 (t, 3 H) ppm.147 469.1 — — — 148 462.2 — — — 151 455.1 — — — 153 513.2 — — — 154499.1 DMSO- 300 δ□ 8.24 (s, 1H), 7.37 (m 2H), 6.28 (m, 1H), 4.27 (br d₆s, 1H), 3.72 (m, 4H), 3.50 (m, 2H), 2.99-2.87 (m, 2H), 2.22 (m, 2H),1.68 (d, 3H), 1.20 (t, 3H), 0.93 (d, 3H) ppm. 155 499.2 — — — 157 445.1— — — 160 486.2 DMSO- 300 δ□ 8.09 (s, 1H), 7.23 (s, 1H), 6.18 (m, 1H),3.78 (m, d₆ 3H), 3.50 (s, 3H), 3.01 (s, 3H), 3.0-2.9 (m, 3H), 2.77 (s,3H), 2.54 (s, 3H), 2.06 (s, 3H), 1.67 (d, 3H), 0.98 (d, 3H) ppm. 162454.1 — — — 168 410.2 — — — 169 425.1 — — — 170 434.2 — — — 171 424.2 —— — 172 487.3 — — — 173 466.2 — — — 175 510.2 — — — 176 536.3 — — — 177517.2 — — — 178 509.2 — — — 180 431.0 — — — 185 452.1 — — — 186 452.2 —— — 187 480.2 — — — 193 386.2 — — — 196 494.2 — — — 197 426.2 — — — 198501.2 — — — 199 480.1 — — — 201 494.2 — — — 202 524.2 — — — 204 483.2 —— — 205 497.2 — — — 206 483.1 — — — 207 497.2 — — — 210 417.3 — — —

Example 212.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile

Step 1. 1-(5-Chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone

The desired compound was prepared according to the procedure of Example13, step 3 to form a racemic intermediate, using iodoethane instead ofiodomethane as the starting material in 90% yield. ¹H NMR (300 MHz,CDCl₃) δ 7.68 (d, J=8.3 Hz, 1H), 3.94 (q, J=7.0 Hz, 2H), 2.61 (s, 3H),1.48 (t, J=7.0 Hz, 3H). LCMS for C₁₀H₁₀ClFIO₂ (M+H)⁺: m/z=342.9, 344.9;Found: 342.9, 344.8.

Step 2. 4-Acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile

A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (7.3g, 21 mmol) in N,N-dimethylformamide (80 mL) was treated with potassiumcyanide (2.1 g, 32 mmol) and stirred at 40° C. for 5 h. The reactionmixture was diluted with ethyl acetate and poured into saturated sodiumbicarbonate solution/water (1:1). The organic layer was separated,washed with saturated sodium bicarbonate solution, dried with magnesiumsulfate, filtered, and concentrated to give a crude brown oil. The crudematerial was purified by flash column chromatography using ethyl acetatein hexanes (0%-30%) to give the desired product (6.1 g, 81%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 1H), 3.93 (q, J=7.0 Hz, 2H),2.61 (s, 3H), 1.47 (t, J=7.0 Hz, 3H). LCMS for C₁₁H₁₀ClINO₂ (M+H)⁺:m/z=349.9; Found: 349.9.

Step 3. tert-Butyl3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate

Zinc (4.60 g, 70.3 mmol) and oven dried Celite (870 mg) was added to aflask and the flask was heated with a heat gun while under high-vac for5 min and then back-filled with nitrogen. N,N-Dimethylacetamide (57 mL)was added, followed by 1,2-dibromoethane (430 μL, 5.0 mmol) and themixture was heated at 70° C. for 10 min and then cooled to roomtemperature. The reaction mixture was treated with chlorotrimethylsilane(630 μL, 5.0 mmol) dropwise and stirred at room temperature for 1 h. Thereaction mixture was treated with a solution of tert-butyl3-iodoazetidine-1-carboxylate (18 g, 62 mmol) in N,N-dimethylacetamide(28 mL) dropwise (internal temperature was kept below 40° C. with awater bath) and heated at 40° C. for 2 h. The zinc-iodo reagent(transferred via canula) was filtered through a plastic filter (that wasappropriately sealed to avoid atmospheric exposure) directly into aclean, dry flask that was flushed with nitrogen. The reaction mixturewas treated with tris(dibenzylideneacetone)dipalladium(0) (720 mg, 0.79mmol) and tri-(2-furyl)phosphine (370 mg, 1.6 mmol) and degassed withnitrogen for a few minutes. The reaction mixture was treated with asolution of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (14 g, 41mmol) in N,N-dimethylacetamide (130 mL) (degassed with nitrogen) quicklyand heated at 70° C. for 2 h. The reaction mixture was poured intosaturated ammonium chloride solution and extracted with ethyl acetate(3×300 mL). The combined organic extracts were washed with water (4×500mL) and brine (1×500 mL), dried with magnesium sulfate, filtered, andconcentrated to a crude dark oil. The crude material was purified byflash column chromatography using ethyl acetate in hexanes (5%-45%) togive the desired product (14 g, 88%). ¹H NMR (300 MHz, CDCl₃) δ 7.46 (s,1H), 4.42-4.20 (m, 5H), 3.80 (q, J=7.0 Hz, 2H), 2.59 (s, 3H), 1.44 (s,9H), 1.37 (t, J=7.0 Hz, 3H). LCMS for C₁₅H₁₆ClN₂O₄ ([M-(t-Bu)+H]+H)⁺:m/z=323.1; Found: 323.0.

Step 4. tert-Butyl3-[3-chloro-2-cyano-6-ethoxy-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate

A solution of(3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(9.7 g, 35 mmol) in tetrahydrofuran (100 mL) was treated with 1.0 Mborane-THF complex in tetrahydrofuran (42 mL, 42 mmol) and stirred at20° C. for 15 min. The reaction mixture was cooled to −30° C. andtreated with a solution of tert-butyl3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate (13g, 35 mmol) in tetrahydrofuran (110 mL) slowly. The flask containing thestarting material ketone was rinsed with additional tetrahydrofuran (20mL) and added to the reaction mixture. The reaction mixture was warmedto 0° C. over a period of 30 min and stirred at 0° C. for 15 min. Thereaction mixture was quenched with water at 0° C., poured into saturatedsodium bicarbonate solution, and extracted with ethyl acetate. Theaqueous layer was separated and extracted with ethyl acetate. Thecombined organic layers were washed with water and brine, dried withmagnesium sulfate, filtered, and concentrated to a crude dark oil. Thecrude material was purified by flash column chromatography using ethylacetate in hexanes (0%-70%) to give the desired product (10.4 g, 78%) asa yellow foam as a 98:2 mixture of enantiomers (Retention times=7.73 minand 9.41 min; ChiralPak AD-H column, 4.6×150 mm, 5 micron particle size,eluting with 5% ethanol in hexanes at 1 ml/min). ¹H NMR (300 MHz, CDCl₃)δ 7.56 (s, 1H), 5.15-5.07 (m, 1H), 4.41-4.17 (m, 5H), 3.74 (q, J=7.0 Hz,2H), 2.12 (d, J=3.7 Hz, 1H), 1.49-1.37 (m, 15H). LCMS for C₁₅H₁₈ClN₂O₄([M-(t-Bu)+H]+H)⁺: m/z=325.1; Found: 325.1.

Step 5. tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate

A solution of tert-butyl3-[3-chloro-2-cyano-6-ethoxy-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate(98:2 mixture of enantiomers from step 4) (10 g, 27 mmol) in methylenechloride (260 mL) at 0° C. was treated with triethylamine (11 mL, 82mmol) followed by methanesulphonic anhydride (7.1 g, 41 mmol) andstirred at 0° C. for 15 min. The reaction mixture was diluted withdichloromethane and washed with water and brine, dried with magnesiumsulfate, filtered, and concentrated to give the crude mesylate that wasused without further purification. A solution of the crude mesylateintermediate in N,N-dimethylformamide (140 mL) was treated with cesiumcarbonate (13 g, 41 mmol) and3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.7 g, 31 mmol) and heatedat 60° C. for 1 h. The reaction mixture was diluted with water andextracted with ethyl acetate (3×250 mL). The combined organic layerswere washed with water and brine, dried with magnesium sulfate,filtered, and concentrated to a crude oil. The crude material waspurified by flash column chromatography (100% dichloromethane to 70%acetonitrile containing 3% methanol/30% dichloromethane) to give thedesired product (8.7 g, 62% for 2 steps) as a yellow foam as a 95:5mixture of enantiomers (RT=4.29 min and 6.00 min; Phenomenex LuxCellulose C-1 column, 4.6×150 mm, 5 micron particle size, eluting with15% ethanol in hexanes at 1 ml/min). This material was separated bychiral HPLC (Phenomenex Lux Cellulose C-1 column, 21.2×250 mm, 5 micronparticle size, eluting with 15% ethanol in hexanes at 10 ml/min) to give7.0 g of the desired peak 1 material (retention time of 8.20 min). ¹HNMR (300 MHz, CDCl₃) δ 8.24 (s, 1H), 7.51 (s, 1H), 6.32 (q, J=7.1 Hz,1H), 5.48 (br s, 2H), 4.40-4.18 (m, 5H), 4.05-3.93 (m, 1H), 3.81-3.65(m, 1H), 2.64 (s, 3H), 1.81 (d, J=7.1 Hz, 3H), 1.48 (t, J=7.0 Hz, 3H),1.43 (s, 9H). LCMS for C₂₅H₃₁ClN₇O₃ (M+H)⁺: m/z=512.2; Found: 512.3.

Step 6.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile

A solution of tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate(peak 1 enantiomer from step 5) (2.2 g, 4.2 mmol) in methylene chloride(11 mL) was treated with trifluoroacetic acid (11 mL) dropwise andstirred at room temperature for 30 min. The reaction mixture wasconcentrated to an oil that was reconcentrated from ethanol (2×) to givea residue. This material was dissolved in a minimum amount of methanol,added dropwise to ice cooled saturated sodium bicarbonate solution (100ml), and extracted several times with 2:1 dichloromethane/isopropanol togive the desired product (1.8 g, quantitative) that was used withoutfurther purification. A small amount of the desired product was purifiedby preparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) to give the desired product. The product was isolated as asingle enantiomer. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.47 (s,1H), 6.23 (q, J=7.0 Hz, 1H), 4.37-4.26 (m, 1H), 3.91-3.61 (m, 6H), 2.54(s, 3H), 1.71 (d, J=7.1 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H). LCMS forC₂₀H₂₃ClN₇O (M+H)⁺: m/z=412.2; Found: 412.1.

Example 213.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(1-methylazetidin-3-yl)benzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile(chiral intermediate in Example 212, Step 6) (0.30 g, 0.73 mmol) inmethanol (7.3 mL) was treated with formaldehyde (37% in water) (0.54 mL,7.3 mmol) and this was stirred at room temperature for 5 min. Thereaction mixture was treated with sodium cyanoborohydride (0.092 g, 1.5mmol) and stirred at room temperature for 2 h. The reaction mixture wasdiluted with methanol and purified by preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) to give the desiredproduct (0.16 g, 50%). The product was isolated as a single enantiomer.¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.48 (s, 1H), 6.27-6.18 (m,1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 2H), 3.83-3.74 (m, 1H), 3.72-3.64(m, 1H), 3.10-2.98 (m, 2H), 2.54 (s, 3H), 2.20 (s, 3H), 1.71 (d, J=6.9Hz, 3H), 1.32 (t, J=6.7 Hz, 3H). LCMS for C₂₁H₂₅ClN₇O (M+H)⁺: m/z=426.2;Found: 426.2.

Example 219.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxyethyl)azetidin-3-yl]benzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile(300 mg, 0.74 mmol, chiral intermediate from Example 212) intetrahydrofuran (14 mL) was treated with triethylamine (260 μL, 1.8mmol) followed by 2-bromoethanol (63 μL, 0.89 mmol) dropwise and stirredat 60° C. for 6 h. The reaction mixture was treated with additional2-bromoethanol (26 μL, 0.37 mmol) and stirred at 60° C. for another 6 h.The reaction mixture was poured into saturated sodium bicarbonatesolution and extracted with ethyl acetate. The organic layer wasconcentrated and purified by preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product (0.15g, 44%). The product was isolated as a single enantiomer. ¹H NMR (400MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.56 (s, 1H), 6.36-6.25 (m, 1H), 4.48 (brs, 1H), 4.19-4.07 (m, 1H), 4.04-3.94 (m, 2H), 3.91-3.82 (m, 1H),3.81-3.72 (m, 1H), 3.20-3.08 (m, 2H), 2.62 (s, 2H), 2.57 (s, 3H), 1.79(d, J=6.8 Hz, 3H), 1.40 (t, J=6.6 Hz, 3H). LCMS for C₂₂H₂₇ClN₇O₂ (M+H)⁺:m/z=456.2; Found: 456.1.

Example 220.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}benzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile(50 mg, 0.12 mmol, chiral intermediate from example 212) in ethanol (1.7mL) was treated with (S)-(−)-methyloxirane (21 μL, 0.30 mmol) and heatedin the microwave at 125° C. for 15 min. The reaction mixture was dilutedwith methanol and purified by preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product (27mg, 47%). The product was isolated as a single diastereomer. ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.48 (s, 1H), 6.23 (q, J=6.9 Hz, 1H), 4.35(d, J=4.5 Hz, 1H), 4.13-3.99 (m, 1H), 3.97-3.88 (m, 2H), 3.85-3.63 (m,2H), 3.61-3.51 (m, 1H), 3.15-2.99 (m, 2H), 2.55 (s, 3H), 2.28 (d, J=5.9Hz, 2H), 1.71 (d, J=7.0 Hz, 3H), 1.32 (t, J=6.9 Hz, 3H), 1.00 (d, J=6.2Hz, 3H). LCMS for C₂₃H₂₉ClN₇O₂ (M+H)⁺: m/z=470.2; Found: 470.2.

Example 236. tert-Butyl2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoate

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile(0.38 g, 0.92 mmol, chiral intermediate from Example 212) inN,N-dimethylformamide (4.6 mL) was treated with potassium carbonate(0.51 g, 3.7 mmol) followed by tert-butyl 2-bromo-2-methylpropanoate(0.86 mL, 4.6 mmol) and heated at 60° C. for 3 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The organiclayer was separated, dried with magnesium sulfate, filtered, andconcentrated to a crude oil. The crude material was purified by flashcolumn chromatography using methanol in dichloromethane (0%-10%) to givethe desired product (0.43 g, 83%). The product was isolated as a singleenantiomer. ¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.44 (s, 1H), 6.22(q, J=6.8 Hz, 1H), 4.12-3.97 (m, 1H), 3.88-3.70 (m, 4H), 3.62-3.48 (m,2H), 2.54 (s, 3H), 1.70 (d, J=7.0 Hz, 3H), 1.33 (t, J=6.9 Hz, 3H), 1.17(s, 9H), 1.05 (s, 6H). LCMS for C₂₈H₃₇ClN₇O₃ (M+H)⁺: m/z=554.3; Found:554.3.

Example 237.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-1,1-dimethylethyl)azetidin-3-yl]benzonitrile

Step 1.2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoicacid bis(trifluoroacetate)

tert-Butyl2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoate(0.36 g, 0.65 mmol, chiral intermediate from Example 236) was dissolvedin a premixed solution of trifluoroacetic acid (3.2 mL)/water (0.065 mL)and stirred at room temperature for 3 h and at 50° C. for 30 min. Thereaction mixture was concentrated and reconcentrated from acetonitrile(2×) to give the desired product as a gum. This gum was treated with asmall amount of methyl-tert-butylether that was swirled until a solidformed. The methyl-tert-butylether was decanted and the residue wasconcentrated to give the desired product (0.51 g, 109%) that was usedwithout further purification. LCMS for C₂₄H₂₉ClN₇O₃ (M+H)⁺: m/z=498.2;Found: 498.3.

Step 2.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-1,1-dimethylethyl)azetidin-3-yl]benzonitrile

A solution of2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoicacid bis(trifluoroacetate) (0.10 g, 0.16 mmol) in tetrahydrofuran (0.9mL) was cooled to −25° C., treated with 4-methylmorpholine (0.072 mL,0.65 mmol) and isobutyl chloroformate (0.085 mL, 0.65 mmol), and stirredat −15° C. for 15 min. The reaction mixture was filtered though adisposable filter cartridge into a separate round bottom flask. Thissolution was then cooled to −20° C. and a solution of sodiumtetrahydroborate (0.031 g, 0.82 mmol) in a minimum amount of water wasadded dropwise. The reaction mixture was stirred at −15° C. for 30 min,poured into water, and extracted with ethyl acetate. The organic layerwas separated, concentrated, diluted with methanol, and purified bypreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired product (3.5 mg, 4%). The product wasisolated as a single enantiomer. ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (s,1H), 7.50 (s, 1H), 7.35 (br s, 2H), 6.23 (q, J=6.7 Hz, 1H), 4.44-4.35(m, 1H), 4.04-3.88 (m, 1H), 3.86-3.73 (m, 1H), 3.72-3.57 (m, 3H), 3.12(d, J=4.7 Hz, 2H), 2.54 (s, 3H), 1.71 (d, J=6.9 Hz, 3H), 1.31 (t, J=6.9Hz, 3H), 0.80 (s, 6H). LCMS for C₂₄H₃₁ClN₇O₂ (M+H)⁺: m/z=484.2; Found:484.2.

Example 239.2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanamide

A solution of2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoicacid bis(trifluoroacetate) (0.05 g, 0.069 mmol, chiral intermediate fromExample 237, Step 1) and 2.0 M ammonia in ethanol (0.17 mL, 0.34 mmol)in N, N-dimethylformamide (1 mL) was treated with triethylamine (0.048mL, 0.35 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.046 g, 0.10 mmol) and stirred at room temperaturefor 1 h. The reaction mixture was quenched with a few drops of water,diluted with methanol, and purified by preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) to give the desiredproduct (25 mg, 73%). The product was isolated as a single enantiomer.¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.51 (s, 1H), 7.23 (s, 1H),6.98 (s, 1H), 6.23 (q, J=7.0 Hz, 1H), 4.09-3.96 (m, 1H), 3.84-3.61 (m,4H), 3.39-3.34 (m, 1H), 3.32-3.28 (m, 1H), 2.54 (s, 3H), 1.71 (d, J=7.0Hz, 3H), 1.31 (t, J=6.9 Hz, 3H), 1.02 (s, 6H). LCMS for C₂₄H₃₀ClN₈O₂(M+H)⁺: m/z=497.2; Found: 497.3.

Example 247.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]benzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile(0.04 g, 0.097 mmol, chiral intermediate from Example 212) and propanoicacid, 2-hydroxy-2-methyl- (0.012 g, 0.12 mmol) in N,N-dimethylformamide(0.54 mL) was treated with triethylamine (0.034 mL, 0.24 mmol) followedby O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.048 g, 0.13 mmol) and stirred at room temperaturefor 30 min. The reaction mixture was diluted with methanol andacetonitrile and purified by preparative LCMS (XBridge C18 column,eluting with a gradient of methanol/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg,14%). The product was isolated as a single enantiomer. ¹H NMR (300 MHz,DMSO-d₆) δ 8.11 (s, 1H), 7.54 (d, J=4.5 Hz, 1H), 6.25 (q, J=7.2 Hz, 1H),5.08 (s, 1H), 4.88-4.77 (m, 1H), 4.73-4.60 (m, 1H), 4.50-4.35 (m, 1H),4.29-4.09 (m, 2H), 3.85-3.73 (m, 2H), 2.55 (s, 3H), 1.73 (d, J=7.0 Hz,3H), 1.37 (t, J=6.3 Hz, 3H), 1.26 (s, 3H), 1.22 (s, 3H). LCMS forC₂₄H₂₉ClN₇O₃ (M+H)⁺: m/z=498.2; Found: 498.2.

Example 261.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile

Step 1. 4-Acetyl-6-chloro-2-iodo-3-methoxybenzonitrile

A solution of 1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone(intermediate from Example 13, Step 3) (18 g, 54 mmol) inN,N-dimethylformamide (200 mL) was treated with potassium cyanide (5.2g, 81 mmol) and stirred at 40° C. for 6 h. The reaction mixture wasdiluted with ethyl acetate and poured into saturated sodium bicarbonatesolution/water (1:1). The organic layer was separated, washed withsaturated sodium bicarbonate solution, dried with magnesium sulfate,filtered, and concentrated to give a crude brown oil. The crude materialwas purified by flash column chromatography using ethyl acetate inhexanes (0%-30%) to give the desired product (11 g, 61%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 7.60 (s, 1H), 3.81 (s, 3H), 2.62 (s,3H). LCMS for C₁₀H₈ClINO₂ (M+H)⁺: m/z=335.9; Found: 335.9.

Step 2. tert-Butyl3-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)azetidine-1-carboxylate

Zinc (5.0 g, 77 mmol) and oven dried Celite (520 mg) was added to aflask and the flask was heated with a heat gun while under high-vac for5 min and then back-filled with nitrogen. N,N-dimethylacetamide (53 mL)was added, followed by 1,2-dibromoethane (400 μL, 4.6 mmol) and themixture was heated at 70° C. for 15 min and then cooled to roomtemperature. The reaction mixture was treated with chlorotrimethylsilane(580 μL, 4.6 mmol) dropwise and stirred at room temperature for 1 h. Thereaction mixture was treated with a solution of tert-butyl3-iodoazetidine-1-carboxylate (16 g, 58 mmol) in N,N-dimethylacetamide(26 mL) dropwise (internal temperature was kept below 40° C. with awater bath) and heated at 40° C. for 2 h. The zinc-iodo reagent(transferred via canula) was filtered through a plastic filter (that wasappropriately sealed to avoid atmospheric exposure) directly into aclean, dry flask that was flushed with nitrogen. The reaction mixturewas treated with tris(dibenzylideneacetone)dipalladium(0) (670 mg, 0.73mmol) and tri-(2-furyl)phosphine (340 mg, 1.5 mmol) and degassed withnitrogen for a few minutes. The reaction mixture was treated with asolution of 4-acetyl-6-chloro-2-iodo-3-methoxybenzonitrile (13 g, 39mmol) in N,N-dimethylacetamide (120 mL) (degassed with nitrogen) quicklyand heated at 70° C. for 2 h. The reaction mixture was poured intosaturated ammonium chloride solution and extracted with ethyl acetate(3×300 mL). The combined organic extracts were washed with water (4×500mL) and brine (1×500 mL), dried with magnesium sulfate, filtered, andconcentrated to a crude dark oil. The crude material was purified byflash column chromatography using ethyl acetate in hexanes (5%-40%) togive the desired product (12 g, 85%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.79(s, 1H), 4.39-4.29 (m, 1H), 4.28-4.11 (m, 4H), 3.68 (s, 3H), 2.58 (s,3H), 1.38 (s, 9H).

Step 3. tert-Butyl3-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate

A solution of(3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(4.3 g, 16 mmol) in tetrahydrofuran (46 mL) was treated with 1.0 Mborane-THF complex in tetrahydrofuran (19 mL, 19 mmol) and stirred at20° C. for 15 min. The reaction mixture was cooled to −30° C. andtreated with a solution of tert-butyl3-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)azetidine-1-carboxylate(5.7 g, 16 mmol) in tetrahydrofuran (49 mL) slowly. The flask containingthe starting material ketone was rinsed with additional tetrahydrofuran(9 mL) and added to the reaction mixture. The temperature of thereaction was −20° C. after the addition was complete. The reactionmixture was warmed to −5° C. over a period of 30 min. The reactionmixture was quenched with water at 0° C., poured into saturated sodiumbicarbonate solution, and extracted with ethyl acetate. The aqueouslayer was separated and extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, dried with magnesiumsulfate, filtered, and concentrated to a crude dark oil. The crudematerial was purified by flash column chromatography using ethyl acetatein hexanes (0%-100%) to give the desired product (5.5 g, 97%) as a beigefoam as a 97:3 mixture of enantiomers (Retention times=12.19 min and13.18 min; Phenomenex Lux Cellulose C-2 column, 4.6×150 mm, 5 micronparticle size, eluting with 8% ethanol in hexanes at 1 ml/min). ¹H NMR(400 MHz, DMSO-d₆) δ 7.62 (s, 1H), 5.48 (d, J=4.6 Hz, 1H), 5.00-4.90 (m,1H), 4.43-4.31 (m, 1H), 4.30-4.10 (m, 4H), 3.66 (s, 3H), 1.38 (s, 9H),1.29 (d, J=6.4 Hz, 3H). LCMS for C₁₄H₁₆ClN₂O₄ ([M-(t-Bu)+H]+H)⁺:m/z=311.1; Found: 311.1.

Step 4. tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate

A solution of tert-butyl3-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate(8.6 g, 23 mmol) (97:3 mixture of enantiomers from step 3) in methylenechloride (220 mL) at 0° C. was treated with triethylamine (8.2 mL, 59mmol) followed by methanesulphonic anhydride (6.1 g, 35 mmol) andstirred at 0° C. for 15 min. The reaction mixture was diluted withdichloromethane and washed with water and brine, dried with magnesiumsulfate, filtered, and concentrated to give the crude mesylate that wasused without further purification. A solution of the crude mesylateintermediate in N,N-dimethylformamide (82 mL) was cooled to 0° C.,treated with sodium hydride (1.2 g, 30 mmol) (60% in mineral oil), andstirred at 0° C. for 30 min. The reaction mixture was treated with asolution of tert-butyl3-(3-chloro-2-cyano-6-methoxy-5-{1-[(methylsulfonyl)oxy]ethyl}phenyl)azetidine-1-carboxylate(11 g, 24 mmol) in N,N-dimethylformamide (170 mL) dropwise over a periodof 10 min and stirred at 0° C. for 30 min and heated at 50° C. for 1 h.The reaction mixture was diluted with water and saturated sodiumbicarbonate solution and extracted with ethyl acetate (3×200 mL). Thecombined organic extracts were washed with water (4×150 mL) and brine,dried with magnesium sulfate, filtered, and concentrated to a crude oil.The crude material was purified by flash column chromatography (2%methanol/98% dichloromethane to 7% methanol/93% dichloromethane [thedichloromethane contained 0.5% triethylamine]) to give the desiredproduct (9.1 g, 77% for 2 steps) as a 9:1 mixture of enantiomers. Thismaterial was separated by chiral HPLC (retention times=5.81 min and 8.94min; Chiracel AD-H column, 20×250 mm, 5 micron particle size, elutingwith 10% ethanol in hexanes at 18 ml/min, 10 mg/inj) to give 6.9 g ofthe desired peak 1 material. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H),7.52 (s, 1H), 6.25 (q, J=7.0 Hz, 1H), 4.45-4.33 (m, 1H), 4.27-4.13 (m,4H), 3.70 (s, 3H), 2.55 (s, 3H), 1.73 (d, J=7.1 Hz, 3H), 1.37 (s, 9H).LCMS for C₂₀H₂₁ClN₇O₃ ([M-(t-Bu)+H]+H)⁺: m/z=442.1; Found: 442.1.

Step 5.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile

A solution of tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate(1.7 g, 3.3 mmol) in methylene chloride (30 mL) was treated withtrifluoroacetic acid (20 mL) and stirred at room temperature for 20 min.The reaction mixture was concentrated to give a residue that was dilutedwith methanol (50 mL) and saturated sodium bicarbonate solution (50 mL).This aqueous solution was diluted with brine (50 mL) and extracted witha 5:1 mixture of dichloromethane/isopropanol (5×100 mL). The combinedorganic extracts were dried over sodium sulfate and concentrated to givethe desired product (1.4 g, 97%). The product was isolated as a singleenantiomer. ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.46 (s, 1H), 7.34(br s, 2H), 6.24 (q, J=6.9 Hz, 1H), 4.40-4.26 (m, 1H), 3.90-3.68 (m,4H), 3.63 (s, 3H), 2.55 (s, 3H), 1.72 (d, J=7.1 Hz, 3H). LCMS forC₁₉H₂₁ClN₇O (M+H)⁺: m/z=398.1; Found: 398.1.

Example 262.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-(1-methylazetidin-3-yl)benzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(chiral intermediate from Example 261) (50 mg, 0.13 mmol) in methanol (3mL) was treated with sodium cyanoborohydride (20 mg, 0.31 mmol) followedby formaldehyde (37% in water) (37 μL, 0.50 mmol) and stirred at roomtemperature for 20 min. The reaction mixture was quenched with aceticacid (170 μL, 2.9 mmol), diluted with methanol, and purified bypreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) to give the desired product (30 mg, 58%). The product wasisolated as a single enantiomer. ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (s,1H), 7.46 (s, 1H), 7.37 (br s, 2H), 6.23 (q, J=7.0 Hz, 1H), 4.10-3.96(m, 1H), 3.95-3.85 (m, 2H), 3.63 (s, 3H), 3.05-2.94 (m, 2H), 2.55 (s,3H), 2.18 (s, 3H), 1.72 (d, J=7.1 Hz, 3H). LCMS for C₂₀H₂₃ClN₇O (M+H)⁺:m/z=412.2; Found: 412.1.

Example 268.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxyethyl)azetidin-3-yl]-3-methoxybenzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(chiral intermediate from Example 261) (400 mg, 1.0 mmol) intetrahydrofuran (14 mL) was treated with triethylamine (350 μL, 2.5mmol) and 2-bromoethanol (85 μL, 1.2 mmol) and stirred at 60° C.overnight. The reaction mixture was concentrated, diluted with methanol,and purified by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product (0.14 g, 31%). Theproduct was isolated as a single enantiomer. ¹H NMR (400 MHz, DMSO-d₆) δ8.11 (s, 1H), 7.46 (s, 1H), 6.24 (q, J=6.9 Hz, 1H), 4.41 (t, J=5.4 Hz,1H), 4.12-4.03 (m, 1H), 3.97-3.88 (m, 2H), 3.64 (s, 3H), 3.38-3.34 (m,2H), 3.09-3.01 (m, 2H), 2.55 (s, 3H), 2.41 (t, J=5.9 Hz, 2H), 1.72 (d,J=7.0 Hz, 3H). LCMS for C₂₁H₂₅ClN₇O₂ (M+H)⁺: m/z=442.2; Found: 442.2.

The compounds of Example 268 and 269 were synthesized from the samechiral intermediate in Example 261. According to the crystal structuredetermination in Example 269, the stereochemistry at the carbon at the1-position of the ethan-1,1-diyl group is S. Because the compound ofExample 268 was synthesized from the same chiral intermediate as Example269, one of ordinary skill in the art would expect that the carbon atthe 1-position of the ethan-1,1-diyl group of Example 268 is also in theS-configuration. Accordingly, it is believed that the compound ofExample 268 is(S)-4-(1-(4-amino-3-methyl-1H-pyrazolo[34-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxyethyl)azetidin-3-yl)-3-methoxybenzonitrile.

Example 269.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(chiral intermediate from Example 261) (2.5 g, 6.3 mmol) in ethanol (130mL) was treated with (S)-(−)-methyloxirane (1.1 mL, 16 mmol) and heatedin the microwave at 120° C. for 25 min. The reaction mixture wasconcentrated to give a residue that was purified by flash columnchromatography using methanol in dichloromethane (0%-10%; methanolcontained 0.5% triethylamine) and by preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) to give the desiredproduct (0.76 g, 26%). The product was isolated as a singlediastereomer. ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.46 (s, 1H),7.34 (br s, 2H), 6.23 (q, J=7.0 Hz, 1H), 4.35 (br s, 1H), 4.14-3.99 (m,1H), 3.98-3.87 (m, 2H), 3.64 (s, 3H), 3.60-3.52 (m, 1H), 3.13-2.99 (m,2H), 2.55 (s, 3H), 2.28 (d, J=5.9 Hz, 2H), 1.75-1.69 (m, 3H), 1.00 (d,J=6.2 Hz, 3H). LCMS for C₂₂H₂₇ClN₇O₂ (M+H)⁺: m/z=456.2; Found: 456.2.

Crystal Structure Determination for the Compound of Example 269

C22,H26,N7,O2,CL1+H₂O

Crystal Data:

C22 H28 Cl F0 N7 O3, from ACN/water, colorless, needle,˜0.500×0.070×0.050 mm, monoclinic, C2, a=25.941(7) Å, b=4.9767(13) Å,c=17.787(5) Å, beta=101.967(4)°, Vol=2246.3(10) Å³, Z=4, T=−100° C.,Formula weight=473.96, Density=1.401 g/cm³, μ(Mo)=0.21 mm-¹

Data Collection:

Bruker SMART APEX-II CCD system, MoKalpha radiation, standard focustube, anode power=50 kV×42 mA, crystal to plate distance=5.0 cm, 512×512pixels/frame, beam center=(256.13, 253.14), total frames=704,oscillation/frame=0.50°, exposure/frame=120.1 sec/frame, SAINTintegration, hkl min/max=(−27, 34, −6, 6, −23, 11), data input toshelx=7578, unique data=5186, two-theta range=3.20 to 56.74°,completeness to two-theta 56.74=99.70%, R(int-xl)=0.0331, SADABScorrection applied.

Solution and Refinement:

Structure solved using XS(Shelxtl), refined using shelxtl softwarepackage, refinement by full-matrix least squares on F², scatteringfactors from Int. Tab. Vol C Tables 4.2.6.8 and 6.1.1.4, number ofdata=5186, number of restraints=2, number of parameters=313,data/parameter ratio=16.57, goodness-of-fit on F²=1.02, Rindices[I>4sigma(I)] R1=0.0524, wR2=0.1033, R indices (all data)R1=0.0826, wR2=0.1162, max difference peak and hole=0.294 and −0.221e/Å³, refined flack parameter=0.05(8), All of the hydrogen atoms exceptthe NH2 and water hydrogens have been idealized using a riding model.

Results:

The asymmetric unit contains one molecule and one water molecule asshown in FIG. 1 with thermal ellipsoids drawn to the 50% probabilitylevel. The predicted structure is confirmed. The absolute configurationis determined based upon the known S configuration at C21. Theconfiguration at C7 is determined to be S. The flack parameter alsoconfirms the correct configuration. Based on the crystal structure, thecompound of Example 269 is believed to be4-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile.The crystal structure is shown in FIG. 1.

TABLE A1 Atomic coordinates (×10{circumflex over ( )}4) and equivalentisotropic displacement parameters (A{circumflex over ( )}2 ×10{circumflex over ( )}3. U(eq) is defined as one third of the trace ofthe orthogonalized Uij tensor. x y z U(eq) Cl(1) 8035(1) 8495(2)  305(1)36(1) N(1) 8519(1) 3404(5) 3463(1) 26(1) O(1) 9561(1) 4043(4) 2906(1)23(1) C(12) 9008(1) 8170(6) 1221(2) 21(1) C(10) 9211(1) 5217(6) 2312(2)20(1) O(2) 11255(1)  1950(5) 2364(1) 29(1) N(4) 9120(1)  528(5) 4287(2)30(1) N(7) 10708(1)  7154(5) 1712(1) 24(1) N(2) 8158(1) 5432(5) 3540(1)24(1) C(9) 8688(1) 4321(6) 2173(2) 20(1) N(3) 9131(1) 1229(5) 5640(2)30(1) C(1) 8205(1) 5793(6) 4289(2) 24(1) C(13) 8494(1) 7215(6) 1069(2)22(1) C(21) 11447(1)  3787(7) 1864(2) 27(1) C(7) 8514(1) 2255(6) 2701(2)21(1) C(14) 8337(1) 5294(6) 1539(2) 23(1) C(16) 9152(1) 10282(7)  751(2) 28(1) C(11) 9384(1) 7106(6) 1834(2) 20(1) C(20) 10994(1) 5251(7) 1322(2) 27(1) C(6) 7877(1) 7848(6) 4574(2) 28(1) C(4) 9278(1) 68(7) 5045(2) 32(1) C(17) 9952(1) 8008(6) 1945(2) 23(1) N(5) 8627(1)4376(6) 6088(2) 30(1) C(18) 10398(1)  6006(7) 2253(2) 27(1) C(19)10208(1)  8201(7) 1229(2) 27(1) N(6) 9263(1) 12004(6)   392(2) 39(1)C(2) 8582(1) 4004(5) 4710(2) 20(1) C(15) 9743(1) 5706(7) 3568(2) 30(1)C(8) 7972(1) 1060(6) 2388(2) 26(1) C(3) 8776(1) 3257(7) 5486(2) 26(1)C(5) 8770(1) 2522(6) 4155(2) 25(1) C(22) 11791(1)  2363(8) 1403(2) 42(1)O(3) 8003(1) 8621(5) 6617(1) 40(1)

TABLE A2 Bond lengths [A] and angles [deg] Cl(1)—C(13) 1.731(3)N(1)—C(5) 1.340(4) N(1)—N(2) 1.403(3) N(1)—C(7) 1.468(4) O(1)—C(10)1.372(3) O(1)—C(15) 1.437(4) C(12)—C(13) 1.390(4) C(12)—C(11) 1.406(4)C(12)—C(16) 1.438(4) C(10)—C(9) 1.400(4) C(10)—C(11) 1.403(4) O(2)—C(21)1.434(4) N(4)—C(5) 1.333(4) N(4)—C(4) 1.345(4) N(7)—C(20) 1.463(4)N(7)—C(18) 1.491(4) N(7)—C(19) 1.494(4) N(2)—C(1) 1.325(4) C(9)—C(14)1.382(4) C(9)—C(7) 1.524(4) N(3)—C(4) 1.329(4) N(3)—C(3) 1.355(4)C(1)—C(2) 1.417(4) C(1)—C(6) 1.485(4) C(13)—C(14) 1.385(4) C(21)—C(22)1.509(4) C(21)—C(20) 1.540(4) C(7)—C(8) 1.522(4) C(16)—N(6) 1.143(4)C(11)—C(17) 1.513(4) C(17)—C(18) 1.538(4) C(17)—C(19) 1.558(4) N(5)—C(3)1.334(4) C(2)—C(5) 1.398(4) C(2)—C(3) 1.417(4) C(5)—N(1)—N(2) 110.6(2)C(5)—N(1)—C(7) 129.0(3) N(2)—N(1)—C(7) 119.5(2) C(10)—O(1)—C(15)116.0(2) C(13)—C(12)—C(11) 120.4(3) C(13)—C(12)—C(16) 119.3(2)C(11)—C(12)—C(16) 120.3(2) O(1)—C(10)—C(9) 117.6(2) O(1)—C(10)—C(11)120.5(2) C(9)—C(10)—C(11) 121.7(3) C(5)—N(4)—C(4) 111.0(3)C(20)—N(7)—C(18) 116.9(2) C(20)—N(7)—C(19) 114.6(2) C(18)—N(7)—C(19)89.10(19) C(1)—N(2)—N(1) 105.8(2) C(14)—C(9)—C(10) 118.9(3)C(14)—C(9)—C(7) 120.7(2) C(10)—C(9)—C(7) 120.4(2) C(4)—N(3)—C(3)117.2(3) N(2)—C(1)—C(2) 110.8(3) N(2)—C(1)—C(6) 119.8(3) C(2)—C(1)—C(6)129.4(3) C(14)—C(13)—C(12) 120.5(3) C(14)—C(13)—C1(1) 119.3(2)C(12)—C(13)—C1(1) 120.2(2) O(2)—C(21)—C(22) 111.0(3) O(2)—C(21)—C(20)111.8(2) C(22)—C(21)—C(20) 110.1(3) N(1)—C(7)—C(8) 108.7(2)N(1)—C(7)—C(9) 111.1(2) C(8)—C(7)—C(9) 114.1(2) C(9)—C(14)—C(13)120.6(3) N(6)—C(16)—C(12) 178.3(3) C(10)—C(11)—C(12) 117.7(2)C(10)—C(11)—C(17) 123.0(3) C(12)—C(11)—C(17) 119.3(2) N(7)—C(20)—C(21)113.9(2) N(3)—C(4)—N(4) 130.3(3) C(11)—C(17)—C(18) 119.6(3)C(11)—C(17)—C(19) 118.7(2) C(18)—C(17)—C(19) 85.1(2) N(7)—C(18)—C(17)89.4(2) N(7)—C(19)—C(17) 88.5(2) C(5)—C(2)—C(3) 116.4(2) C(5)—C(2)—C(1)105.1(2) C(3)—C(2)—C(1) 138.3(3) N(5)—C(3)—N(3) 116.5(3) N(5)—C(3)—C(2)124.7(3) N(3)—C(3)—C(2) 118.8(3) N(4)—C(5)—N(1) 126.1(3) N(4)—C(5)—C(2)126.3(3) N(1)—C(5)—C(2) 107.6(2)

TABLE A3 Anisotropic displacement parameters (A{circumflex over ( )}2 ×10{circumflex over ( )}3). The anisotropic displacement factor exponenttakes the form: −2 pi{circumflex over ( )}2 [h{circumflex over ( )}2a*{circumflex over ( )}2 U11 + . . . + 2 h k a* b* U12] U11 U22 U33 U23U13 U12 Cl(1) 28(1) 47(1) 29(1) 14(1)  0(1) 2(1) N(1) 29(1) 25(1) 24(1)4(1) 8(1) 2(1) C(12) 24(1) 17(1) 22(1) 2(1) 3(1) 1(1) C(10) 22(1) 18(1)19(1) 0(1) 6(1) 8(1) O(2) 32(1) 29(1) 27(1) −3(1)  8(1) −4(1)  N(4)30(1) 23(1) 36(2) 6(1) 9(1) 4(1) N(7) 22(1) 26(1) 27(1) −3(1)  7(1)−1(1)  N(2) 26(1) 20(1) 29(1) 2(1) 11(1)  1(1) C(9) 23(1) 18(1) 21(1)−1(1)  10(1)  6(1) N(3) 31(1) 31(1) 28(2) 4(1) 2(1) 3(1) C(1) 26(2)21(2) 28(2) 1(1) 9(1) −3(1)  C(13) 25(1) 25(2) 17(1) 6(1) 6(1) 8(1)C(21) 23(1) 29(2) 32(2) −2(2)  11(1)  −2(1)  C(7) 25(1) 18(1) 22(2) 0(1)8(1) 4(1) C(14) 23(1) 23(2) 25(2) 1(1) 8(1) 1(1) C(16) 26(2) 31(2) 25(2)4(1) 5(1) 2(1) C(11) 22(1) 19(1) 21(1) −4(1)  7(1) −2(1)  C(20) 26(2)30(2) 27(2) −5(1)  9(1) −7(1)  C(6) 30(2) 18(2) 39(2) −2(1)  10(1) −1(1)  C(4) 26(2) 30(2) 37(2) 5(2) 3(2) 6(1) C(17) 22(1) 22(2) 25(2)−3(1)  3(1) −4(1)  N(5) 36(2) 32(2) 23(2) 0(1) 7(1) −1(1)  C(18) 26(2)33(2) 26(2) 1(1) 10(1)  3(1) C(19) 27(1) 28(2) 25(2) 6(1) 5(1) −3(1) N(6) 42(2) 36(2) 39(2) 14(1)  8(1) −2(1)  C(2) 18(1) 15(1) 25(2) 3(1)3(1) −5(1)  C(15) 30(2) 35(2) 22(2) −8(1)  2(1) 1(1) C(8) 31(2) 20(1)29(2) 3(1) 11(1)  −1(1)  C(3) 27(1) 26(2) 26(2) 3(1) 5(1) −4(1)  C(5)27(2) 21(2) 26(2) 4(1) 5(1) −3(1)  C(22) 37(2) 43(2) 48(2) −7(2)  17(2) 4(2) O(3) 31(1) 37(1) 52(2) −4(1)  5(1) 3(1)

TABLE A4 Hydrogen coordinates (×10{circumflex over ( )}4) and isotropicdisplacement parameters (A{circumflex over ( )}2 × 10{circumflex over( )}3) x y z U(eq) H(21A) 11662 5142 2184 33 H(7A) 8769 778 2769 25H(14A) 7993 4654 1427 28 H(20A) 11136 6209 936 32 H(20B) 10747 3924 105932 H(6A) 7658 8739 4146 43 H(6B) 8102 9141 4882 43 H(6C) 7660 6994 488043 H(4A) 9529 −1277 5173 38 H(17A) 10005 9684 2240 28 H(18A) 10560 62712791 33 H(18B) 10299 4141 2151 33 H(19A) 10051 7013 811 32 H(19B) 1023510021 1045 32 H(15A) 9984 4705 3948 45 H(15B) 9448 6265 3778 45 H(15C)9918 7259 3420 45 H(8A) 7888 −221 2748 39 H(8B) 7971 182 1907 39 H(8C)7713 2467 2310 39 H(22C) 12072 1453 1746 62 H(22D) 11937 3652 1104 62H(22A) 11584 1079 1067 62 H(5) 8394(11) 5640(60) 6006(16) 11(7)  H(5′)8756(12) 3720(80) 6590(20) 43(10) H(2″) 11091(16)   700(100) 2100(30)66(15) H(3) 8231(15) 9740(80) 6910(20) 80(17) H(3′) 7658(11) 9010(80)6510(20) 52(12)

TABLE A5 Torsion angles [deg] C(15)—O(1)—C(10)—C(9) −109.6(3)C(15)—O(1)—C(10)—C(11)  74.8(3) C(5)—N(1)—N(2)—C(1)   1.3(3)C(7)—N(1)—N(2)—C(1)  171.4(2) O(1)—C(10)—C(9)—C(14) −174.4(2)C(11)—C(10)—C(9)—C(14)   1.1(4) O(1)—C(10)—C(9)—C(7)   4.1(4)C(11)—C(10)—C(9)—C(7)  179.6(2) N(1)—N(2)—C(1)—C(2)  −1.2(3)N(1)—N(2)—C(1)—C(6)  179.4(2) C(11)—C(12)—C(13)—C(14)   3.0(4)C(16)—C(12)—C(13)—C(14) −176.2(3) C(11)—C(12)—C(13)—C1(1) −179.0(2)C(16)—C(12)—C(13)—C1(1)   1.7(4) C(5)—N(1)—C(7)—C(8)  109.1(3)N(2)—N(1)—C(7)—C(8)  −58.9(3) C(5)—N(1)—C(7)—C(9) −124.6(3)N(2)—N(1)—C(7)—C(9)  67.4(3) C(14)—C(9)—C(7)—N(1) −112.9(3)C(10)—C(9)—C(7)—N(1)  68.6(3) C(14)—C(9)—C(7)—C(8)  10.4(4)C(10)—C(9)—C(7)—C(8) −168.1(3) C(10)—C(9)—C(14)—C(13)  −2.9(4)C(7)—C(9)—C(14)—C(13)  178.6(3) C(12)—C(13)—C(14)—C(9)   0.8(4)C1(1)—C(13)—C(14)—C(9) −177.1(2) C(13)—C(12)—C(16)—N(6)    98(12)C(11)—C(12)—C(16)—N(6)   −82(12) O(1)—C(10)—C(11)—C(12)  178.0(3)C(9)—C(10)—C(11)—C(12)   2.6(4) O(1)—C(10)—C(11)—C(17)  −1.4(4)C(9)—C(10)—C(11)—C(17) −176.8(3) C(13)—C(12)—C(11)—C(10)  −4.6(4)C(16)—C(12)—C(11)—C(10)  174.6(3) C(13)—C(12)—C(11)—C(17)  174.7(3)C(16)—C(12)—C(11)—C(17)  −6.0(4) C(18)—N(7)—C(20)—C(21)  −66.6(3)C(19)—N(7)—C(20)—C(21) −168.9(2) O(2)—C(21)—C(20)—N(7)  68.8(3)C(22)—C(21)—C(20)—N(7) −167.3(3) C(3)—N(3)—C(4)—N(4)  −1.9(5)C(5)—N(4)—C(4)—N(3)   1.5(5) C(10)—C(11)—C(17)—C(18)  33.6(4)C(12)—C(11)—C(17)—C(18) −145.8(3) C(10)—C(11)—C(17)—C(19)  135.1(3)C(12)—C(11)—C(17)—C(19)  −44.3(4) C(20)—N(7)—C(18)—C(17) −138.9(2)C(19)—N(7)—C(18)—C(17)  −21.5(2) C(11)—C(17)—C(18)—N(7)  141.1(2)C(19)—C(17)—C(18)—N(7)  20.7(2) C(20)—N(7)—C(19)—C(17)  140.7(2)C(18)—N(7)—C(19)—C(17)  21.3(2) C(11)—C(17)—C(19)—N(7) −141.9(3)C(18)—C(17)—C(19)—N(7)  −20.7(2) N(2)—C(1)—C(2)—C(5)   0.6(3)C(6)—C(1)—C(2)—C(5)  179.9(3) N(2)—C(1)—C(2)—C(3) −173.9(3)C(6)—C(1)—C(2)—C(3)   5.4(6) C(4)—N(3)—C(3)—N(5)  179.0(3)C(4)—N(3)—C(3)—C(2)   0.4(4) C(5)—C(2)—C(3)—N(5) −177.4(3)C(1)—C(2)—C(3)—N(5)  −3.3(5) C(5)—C(2)—C(3)—N(3)   1.2(4)C(1)—C(2)—C(3)—N(3)  175.3(3) C(4)—N(4)—C(5)—N(1) −177.0(3)C(4)—N(4)—C(5)—C(2)   0.4(4) N(2)—N(1)—C(5)—N(4)  176.9(3)C(7)—N(1)—C(5)—N(4)   8.0(5) N(2)—N(1)—C(5)—C(2)  −1.0(3)C(7)—N(1)—C(5)—C(2) −169.9(3) C(3)—C(2)—C(5)—N(4)  −1.7(4)C(1)—C(2)—C(5)—N(4) −177.6(3) C(3)—C(2)—C(5)—N(1)  176.2(2)C(1)—C(2)—C(5)—N(1)   0.2(3)

Examples 272 and 273. Diastereoisomers of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxy-1-methylethyl)azetidin-3-yl]-3-methoxybenzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(40 mg, 0.10 mmol) in methanol (2 mL) was treated with sodiumcyanoborohydride (16 mg, 0.25 mmol) followed by acetol (28 μL, 0.40mmol) and stirred at room temperature for 1 h. The reaction mixture wasquenched with acetic acid (100 μL, 1.8 mmol), diluted with methanol, andpurified by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired products as a mixture ofdiastereoisomers. This mixture of diastereoisomers was separated bychiral HPLC (RT=3.70 min and 6.58 min; Phenomenex Lux Cellulose C-4column, 21.2×250 mm, 5 micron particle size, eluting with 20% ethanol inhexanes at 18 ml/min, 5 mg/inj) to give the desired peak 1 isomer(compound 272) (19 mg, 41%) and peak 2 isomer (compound 273) (23 mg,50%) Peak 1: ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.47 (s, 1H),7.34 (br s, 2H), 6.24 (q, J=6.9 Hz, 1H), 4.43 (t, J=5.2 Hz, 1H),4.07-3.82 (m, 3H), 3.64 (s, 3H), 3.31-3.24 (m, 1H), 3.17-3.06 (m, 2H),3.06-2.97 (m, 1H), 2.55 (s, 3H), 2.21-2.11 (m, 1H), 1.72 (d, J=7.1 Hz,3H), 0.81 (d, J=6.3 Hz, 3H). LCMS for C₂₂H₂₇ClN₇O₂ (M+H)⁺: m/z=456.2;Found: 456.2. Peak 2: ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.47 (s,1H), 7.35 (br s, 2H), 6.24 (q, J=7.0 Hz, 1H), 4.43 (t, J=5.5 Hz, 1H),4.06-3.91 (m, 2H), 3.89-3.79 (m, 1H), 3.64 (s, 3H), 3.30-3.24 (m, 1H),3.15-3.00 (m, 3H), 2.55 (s, 3H), 2.21-2.10 (m, 1H), 1.72 (d, J=7.1 Hz,3H), 0.82 (d, J=6.2 Hz, 3H). LCMS for C₂₂H₂₇ClN₇O₂ (M+H)⁺: m/z=456.2;Found: 456.2.

Example 281.2-(1-Acetylazetidin-3-yl)-4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxybenzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(chiral intermediate from Example 261) (60 mg, 0.15 mmol) intetrahydrofuran (2 mL) at 0° C. was treated with triethylamine (53 μL,0.38 mmol) followed by acetyl chloride (13 μL, 0.18 mmol) and stirred at20° C. overnight. The reaction mixture was diluted with methanol andpurified by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product (39 mg, 59%). Theproduct was isolated as a single enantiomer. ¹H NMR (300 MHz, DMSO-d₆) δ8.11 (s, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.36 (br s, 2H), 6.26 (q, J=7.0Hz, 1H), 4.57-4.36 (m, 3H), 4.30-4.21 (m, 1H), 4.18-4.08 (m, 1H), 3.71(d, J=3.1 Hz, 3H), 2.55 (s, 3H), 1.78-1.71 (m, 6H). LCMS forC₂₁H₂₃ClN₇O₂ (M+H)⁺: m/z=440.2; Found: 440.1.

Example 285.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1-(methylsulfonyl)azetidin-3-yl]benzonitrile

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(chiral intermediate from Example 261) (40 mg, 0.10 mmol) indichloromethane (1 mL) was treated with triethylamine (35 μL, 0.25mmol), cooled to 0° C., treated with methanesulfonyl chloride (9.3 μL,0.12 mmol) and stirred at 0° C. for 1 h. The reaction mixture wasdiluted with methanol and purified by preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) to give the desiredproduct (20 mg, 42%). The product was isolated as a single enantiomer.¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.35 (br s, 2H),6.25 (q, J=7.0 Hz, 1H), 4.54-4.40 (m, 1H), 4.27-4.12 (m, 4H), 3.68 (s,3H), 3.01 (s, 3H), 2.55 (s, 3H), 1.74 (d, J=7.1 Hz, 3H). LCMS forC₂₀H₂₃ClN₇O₃S (M+H)⁺: m/z=476.1; Found: 476.1.

Example 289. Methyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(chiral intermediate from Example 261) (20 mg, 0.05 mmol) indichloromethane (1 mL) was treated with triethylamine (20 μL, 0.14 mmol)followed by methyl chloroformate (4.7 μL, 0.06 mmol) and stirred at roomtemperature for 1 h. The reaction mixture was diluted with methanol andpurified by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product (12 mg, 52%). Theproduct was isolated as a single enantiomer. ¹H NMR (300 MHz, DMSO-d₆) δ8.11 (s, 1H), 7.51 (s, 1H), 7.34 (br s, 2H), 6.25 (q, J=7.0 Hz, 1H),4.53-4.38 (m, 1H), 4.36-4.17 (m, 4H), 3.71 (s, 3H), 3.55 (s, 3H), 2.55(s, 3H), 1.73 (d, J=7.1 Hz, 3H). LCMS for C₂₁H₂₃ClN₇O₃ (M+H)⁺:m/z=456.2; Found: 456.1.

Example 292.3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N-(tert-butyl)azetidine-1-carboxamide

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(chiral intermediate from Example 261) (20 mg, 0.05 mmol) inN,N-dimethylformamide (1 mL) was treated with triethylamine (20 μL, 0.14mmol) followed by 2-isocyanato-2-methyl-propane (7.2 μL, 0.063 mmol) andstirred at room temperature overnight. The reaction mixture was dilutedwith methanol and purified by preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product (16mg, 64%). The product was isolated as a single enantiomer. LCMS forC₂₄H₃₀ClN₈O₂ (M+H)⁺: m/z=497.2; Found: 497.2.

Example 293.3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxamide

A solution of3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N-(tert-butyl)azetidine-1-carboxamide(chiral intermediate from Example 292) (16 mg, 0.032 mmol) intrifluoroacetic acid (2 mL) was heated in the microwave at 120° C. for10 min. The reaction mixture was diluted with methanol and purified bypreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) to give the desired product (7 mg, 50%). The product wasisolated as a single enantiomer. ¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (s,1H), 7.62 (s, 1H), 7.35 (br s, 2H), 6.28 (q, J=6.9 Hz, 1H), 5.70 (br s,1H), 4.62-4.49 (m, 1H), 4.34-4.20 (m, 1H), 3.83 (s, 3H), 3.78-3.49 (m,2H), 2.55 (s, 3H), 1.73 (d, J=7.0 Hz, 3H). LCMS for C₂₀H₂₂ClN₈O₂ (M+H)⁺:m/z=441.2; Found: 441.1.

Example 296.3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N,N-dimethylazetidine-1-carboxamide

A solution of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile(chiral intermediate from Example 261) (40 mg, 0.10 mmol) inN,N-dimethylformamide (2 mL) was treated with triethylamine (40 μL, 0.29mmol) followed by p-nitrophenyl chloroformate (23 μL, 0.13 mmol) andstirred at room temperature for 1 h. The reaction mixture was dilutedwith methanol and purified by preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product thatwas used immediately. A solution of the p-nitrophenyl carbamateintermediate in tetrahydrofuran (1 mL) was treated with triethylamine(15 μL, 0.11 mmol) followed by a solution of 1.0 M dimethylamine intetrahydrofuran (150 μL, 0.15 mmol) and heated in a sealed tube at 60°C. for 2 h. The reaction mixture was concentrated, diluted with methanoland purified by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product (13 mg, 28%). Theproduct was isolated as a single enantiomer. ¹H NMR (300 MHz, DMSO-d₆) δ8.11 (s, 1H), 7.49 (s, 1H), 7.36 (br s, 2H), 6.25 (q, J=7.0 Hz, 1H),4.44-4.23 (m, 3H), 4.22-4.10 (m, 2H), 3.69 (s, 3H), 2.76 (s, 6H), 2.55(s, 3H), 1.73 (d, J=7.1 Hz, 3H). LCMS for C₂₂H₂₆ClN₈O₂ (M+H)⁺:m/z=469.2; Found: 469.1.

Example 298.1-{1-[4,5-Dichloro-3-(1-ethylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1. 1-(4,5-Dichloro-2-hydroxyphenyl)ethanone

A solution of 3,4-dichlorophenol [AK Scientific] (30 g, 18 mmol) inacetyl chloride (19 mL, 270 mmol) was stirred at 60° C. for 2 h. Thereaction mixture was cooled to 20° C., treated with aluminum trichloride(37 g, 280 mmol) portionwise, and heated at 180° C. for 30 min. Thereaction mixture was cooled to 20° C. and the solution hardened into asolid block that was not easy to break apart. This material was cooledto 0° C. and quenched slowly with 1 M HCl in portions. The solid blockof material slowly broke apart with enough HCl and this heterogenousmixture was stirred at 20° C. overnight to ensure uniformity. The solidwas filtered, washed with copious amounts of water, and dried undervacuum to give the desired product (38 g, quantitative) as a tan solid.

Step 2. 1-(4,5-Dichloro-2-hydroxy-3-iodophenyl)ethanone

A solution of 1-(4,5-dichloro-2-hydroxyphenyl)ethanone (12 g, 59 mmol)in acetic acid (70 mL) was treated with N-iodosuccinimide (16 g, 71mmol) and stirred at 90° C. for 18 h. The reaction mixture was treatedwith additional N-iodosuccinimide (8 g, 36 mmol) and stirred at 90° C.for 4 h. The reaction mixture was concentrated, diluted with ethylacetate, and quenched with saturated sodium bicarbonate until thebubbling stopped. The organic layer was separated and the aqueous wasre-extracted with ethyl acetate. The combined organic layers were driedand concentrated to give a brown solid. This material was recrystallizedfrom methanol to give desired product (9.0 g, 46%) as a tan solid. ¹HNMR (300 MHz, CDCl₃) δ 13.36 (s, 1H), 7.85 (s, 1H), 2.65 (s, 3H). LCMSfor C₈H₆Cl₂IO₂ (M+H)⁺: m/z=330.9, 332.9; Found: 330.8, 332.9.

Step 3. 1-(4,5-Dichloro-3-iodo-2-methoxyphenyl)ethanone

A solution of 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (16 g, 47mmol) and potassium carbonate (17 g, 120 mmol) in N,N-dimethylformamide(40 mL) was treated with methyl iodide (6.4 mL, 100 mmol) and stirred at60° C. for 1 h. The reaction mixture was diluted with water andextracted with ethyl acetate (2×). The combined organic layers weredried with magnesium sulfate, filtered, and concentrated to give a crudesolid. The crude material was purified by flash column chromatographyusing ethyl acetate in hexanes (5%-30%) to give the desired product (14g, 84%) as an orange solid. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (s, 1H), 3.79(s, 3H), 2.60 (s, 3H). LCMS for C₉H₈Cl₂IO₂ (M+H)⁺: m/z=344.9, 346.9;Found: 344.8, 346.9.

Step 4. tert-Butyl3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-1-carboxylate

Zinc (4.5 g, 69 mmol) was suspended with 1,2-dibromoethane (420 μL, 4.9mmol) in N,N-dimethylformamide (54 mL). The mixture was heated at 70° C.for 10 min and then cooled to room temperature. Chlorotrimethylsilane(620 μL, 4.9 mmol) was added dropwise and stirring was continued for 1h. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (17 g, 61mmol) in N,N-dimethylformamide (30 mL) was then added and the mixturewas heated at 40° C. for 1 h before a mixture of1-(4,5-dichloro-3-iodo-2-methoxyphenyl)ethanone (14 g, 41 mmol),tris(dibenzylideneacetone)dipalladium(0) (710 mg, 0.77 mmol) andtri-(2-furyl)phosphine (360 mg, 1.6 mmol) in N,N-dimethylformamide (120mL) was added quickly. The reaction mixture was stirred overnight atroom temperature. The reaction mixture was then partitioned betweenethyl acetate and saturated ammonium chloride solution. The organiclayer was washed with water, dried with magnesium sulfate, filtered, andconcentrated to a crude residue that was purified by flash columnchromatography using ethyl acetate in hexanes (0%-25%) to give thedesired product (12 g, 77%). LCMS for C₁₇H₂₁Cl₂NO₄Na (M+Na)⁺: m/z=396.1;Found: 396.0.

Step 5. tert-Butyl3-[2,3-dichloro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate

A solution of tert-butyl3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-1-carboxylate (9.6 g,26 mmol) in methanol (240 mL) at 0° C. was treated with sodiumtetrahydroborate (1.9 g, 51 mmol) portionwise over 5 min and stirred at0° C. for 30 min. The reaction mixture was quenched with acetic acid(7.3 mL, 130 mmol) at 0° C. and treated with saturated sodiumbicarbonate solution (˜50 mL). The reaction mixture was concentrated toremove most of the methanol (to ˜60 mL), poured into saturated sodiumbicarbonate solution (150 ml), and extracted with ethyl acetate (2×200mL). The combined organic extracts were washed with water and brine,dried over sodium sulfate, filtered, and concentrated to give thedesired product (9.6 g, quantitative) that was used without furtherpurification. LCMS for C₁₃H₁₆Cl₂NO₄ ([M-(t-Bu)+H]+H)⁺: m/z=320.0; Found:320.0.

Step 6. tert-Butyl3-[2,3-dichloro-5-(1-chloroethyl)-6-methoxyphenyl]azetidine-1-carboxylate

N,N-Dimethylformamide (0.92 mL, 12 mmol) was added to solid cyanuricchloride (2.2 g, 12 mmol) at room temperature (DMF is absorbed by thesolid). The mixture was allowed to stand for 10 min, treated withmethylene chloride (60 mL), and stirred for a few minutes to break upthe solid. The reaction mixture was treated with a solution oftert-butyl3-[2,3-dichloro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate(3.0 g, 8.0 mmol) in methylene chloride (30 mL) and stirred at 35-40° C.for 2 h. The reaction mixture was treated with additionalN,N-dimethylformamide (1 mL) and stirred at 35-40° C. for 4 h. Thereaction required another treatment of N,N-dimethylformamide (1 mL) withstirring at 35-40° C. overnight to proceed to completion. The reactionmixture was diluted with water and dichloromethane. The organic phasewas separated and washed with saturated sodium bicarbonate solution,water and brine, dried over magnesium sulfate, filtered, andconcentrated to a crude residue. The crude material was purified byflash column chromatography using ethyl acetate in hexanes (5%-40%) togive the desired product (2.8 g, 90%). LCMS for C₁₃H₁₅Cl₃NO₃([M-(t-Bu)+H]+H)⁺: m/z=338.0, 340.0; Found: 337.9, 339.9.

Step 7. tert-Butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5,6-dichloro-2-methoxyphenyl}azetidine-1-carboxylate

A solution of tert-butyl3-[2,3-dichloro-5-(1-chloroethyl)-6-methoxyphenyl]azetidine-1-carboxylate(1.0 g, 2.5 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.43g, 2.9 mmol) in N,N-dimethylformamide (23 mL) was treated with cesiumcarbonate (1.2 g, 3.8 mmol) and potassium iodide (42 mg, 0.25 mmol) andheated at 100° C. for 10 h. The reaction mixture was diluted with ethylacetate (75 mL) and water (75 mL). The aqueous layer was separated andreextracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with water, saturated sodium bicarbonate solution, andbrine, dried over magnesium sulfate, filtered, and concentrated to acrude residue. The crude material was purified by flash columnchromatography using methanol in dichloromethane (0%-10%) to give thedesired product (0.97 g, 75%). LCMS for C₂₃H₂₉Cl₂N₆O₃ (M+H)⁺: m/z=507.2,509.2; Found: 507.0, 509.0.

Step 8.1-[1-(3-Azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A solution of tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5,6-dichloro-2-methoxyphenyl}azetidine-1-carboxylate(0.97 g, 1.9 mmol) in methylene chloride (20 mL) was treated withtrifluoroacetic acid (10 mL) and stirred at 20° C. for 30 min. Thereaction mixture was concentrated and the residue was diluted withmethanol (˜20 mL) and treated with saturated sodium bicarbonate solution(to pH˜8). The reaction mixture was concentrated to remove the methanol.The oil that was suspended in the aqueous layer was extracted into a 5:1mixture of dichloromethane/isopropanol, dried over magnesium sulfate,filtered, and concentrated to give the desired product (0.77 g, 99%)that was used in the next step without further purification. LCMS forC₁₈H₂₁Cl₂N₆O (M+H)⁺: m/z=407.1, 409.1; Found: 407.0, 409.0.

Step 9.1-{1-[4,5-Dichloro-3-(1-ethylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A solution of1-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(40 mg, 0.098 mmol) in methanol (2.6 mL) was treated with sodiumcyanoborohydride (15 mg, 0.25 mmol) followed by acetaldehyde (22 μL,0.39 mmol) and stirred at 20° C. for 20 min. The reaction mixture wasquenched with acetic acid (130 μL, 2.3 mmol), diluted with methanol, andpurified by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product as a mixture ofenantiomers. This racemic mixture was separated by chiral HPLC (RT=18.6min and 22.0 min; Phenomenex Lux Cellulose C-4 column, 21.2×250 mm, 5micron particle size, eluting with 5% ethanol in hexanes at 18 ml/min,2.5 mg/inj) to give the desired peak 1 isomer (11 mg, 26%). ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.45 (s, 1H), 7.33 (br s, 2H), 6.21 (q,J=6.9 Hz, 1H), 3.98-3.77 (m, 3H), 3.57 (s, 3H), 2.92-2.83 (m, 1H),2.79-2.72 (m, 1H), 2.55 (s, 3H), 2.35-2.22 (m, 2H), 1.70 (d, J=7.1 Hz,3H), 0.86 (t, J=7.1 Hz, 3H). LCMS for C₂₀H₂₅Cl₂N₆O (M+H)⁺: m/z=435.1;Found: 435.0.

Example 307.4-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-6-chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)benzonitrile

Step 1. tert-Butyl3-{3-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate

The desired compound was prepared according to the procedure of Example212, step 5 (chiral intermediate), using5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ACES Pharma] instead of3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as the starting material in18% yield. ¹H NMR (500 MHz, CDCl₃) δ 8.13 (s, 1H), 6.93 (br s, 1H), 6.79(s, 1H), 6.17 (q, J=7.1 Hz, 1H), 5.24 (s, 2H), 4.40-4.27 (m, 4H),4.27-4.18 (m, 1H), 4.03-3.92 (m, 1H), 3.80-3.70 (m, 1H), 2.43 (s, 3H),1.74 (d, J=7.1 Hz, 3H), 1.43 (s, 9H), 1.40 (t, J=7.0 Hz, 3H). LCMS forC₂₆H₃₂ClN₆O₃ (M+H)⁺: m/z=511.2; Found: 511.2.

Step 2.4-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile

The desired compound was prepared according to the procedure of Example212, step 6, using tert-butyl3-{3-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylateinstead of tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylateas the starting material in 99% yield. LCMS for C₂₁H₂₄ClN₆O (M+H)⁺:m/z=411.2; Found: 411.1.

Step 3.4-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-6-chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)benzonitrile

The desired compound was prepared according to the procedure of Example213 using4-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrileinstead of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrileand acetone instead of formaldehyde as the starting materials in 65%yield. The product was isolated as a single enantiomer. ¹H NMR (300 MHz,dmso) δ 7.95 (s, 1H), 7.19 (s, 1H), 7.16-7.13 (m, 1H), 6.58 (s, 2H),6.11 (q, J=7.1 Hz, 1H), 4.04-3.67 (m, 5H), 3.04-2.92 (m, 2H), 2.36 (s,3H), 2.27-2.12 (m, 1H), 1.69 (d, J=7.1 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H),0.85 (dd, J=6.1, 1.8 Hz, 6H). LCMS for C₂₄H₃₀ClN₆O (M+H)⁺: m/z=453.2;Found: 453.3.

Compounds Synthesized

Experimental procedures for compound Examples 214-218, 221-235, 238,240-246, 248-260, 263-267, 270, 271, 274-280, 282-284, 286-288, 290,291, 294, 295, 297, 299-306, 308, and 309 are summarized in Tables 4 and5.

TABLE 4

Ex. No. Name R² R⁴ R⁵ R⁶ Salt Proc.¹ 214 4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-6-chloro-3-ethoxy-2-(1-ethylazetidin-3-yl)benzonitrile³ Et CN Cl

— 213 215 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(1- isopropylazetidin-3-yl)benzonitrile³Et CN Cl

— 213 216 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(1- isobutylazetidin-3-yl)benzonitrile³ EtCN Cl

— 213 217 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1- (cyclopropylmethyl)azetidin-3-yl]-3-ethoxybenzonitrile³ Et CN Cl

— 213 218 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-(1- cyclobutylazetidin-3-yl)-3- ethoxybenzonitrile³Et CN Cl

— 213 221 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-{1- [(2R)-2-hydroxypropyl]azetidin-3-yl}benzonitrile⁵ Et CN Cl

— 220 222 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (2-hydroxy-2- methylpropyl)azetidin-3-yl]benzonitrile³ Et CN Cl

— 220 223 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (2-hydroxy-1-methylethyl)azetidin- EtCN Cl

— 272/273 3-yl]benzonitrile (from peak 1)⁵ 2244-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (2-hydroxy-1-methylethyl)azetidin- EtCN Cl

— 272/273 3-yl]benzonitrile (from peak 2)⁵ 2254-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (2-methoxyethyl)azetidin-3- Et CN Cl

— 213 yl]benzonitrile³ 226 4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-6-chloro-3-ethoxy-2-{1-[2-methoxy-1- Et CN Cl

— 213 (methoxymethyl)ethyl]azetidin-3- yl}benzonitrile³ 2274-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (tetrahydrofuran-3-yl)azetidin-3-yl]benzonitrile (from peak 1)⁵ Et CN Cl

— 272/273 228 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (tetrahydrofuran-3-yl)azetidin-3-yl]benzonitrile (from peak 2)⁵ Et CN Cl

— 272/273 229 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (tetrahydro-2H-pyran-4-yl)azetidin-3-yl]benzonitrile³ Et CN Cl

— 213 230 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (tetrahydrofuran-3-ylmethyl)azetidin-3-yl]benzonitrile (from peak 1)⁵ Et CN Cl

— 272/273 231 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (tetrahydrofuran-3-ylmethyl)azetidin-3-yl]benzonitrile (from peak 2)⁵ Et CN Cl

— 272/273 232 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (tetrahydro-2H-pyran-4-ylmethyl)azetidin-3-yl]benzonitrile³ Et CN Cl

— 213 233 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (2,2,2-trifluoroethyl)azetidin-3- EtCN Cl

— 219 yl]benzonitrile³ 234 4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-6-chloro-3-ethoxy-2-[1-(3,3,3-trifluoropropyl)azetidin-3- Et CN Cl

— 213 yl]benzonitrile³ 235 4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-6-chloro-2-[1-(cyanomethyl)azetidin-3-yl]-3- Et CN Cl

— 219 ethoxybenzonitrile³ 238 Ethyl 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1- yl)-2-methylpropanoate³ Et CN Cl

— 236 240 2-(3-{3-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}azetidin-1-yl)-N,2-dimethylpropanamide³ Et CN Cl

— 239 241 2-(3-{3-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}azetidin-1-yl)-N,N,2-trimethylpropanamide³ Et CN Cl

— 239 242 2-(1-Acetylazetidin-3-yl)-4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxybenzonitrile³ Et CN Cl

— 281 243 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(1- propionylazetidin-3-yl)benzonitrile³Et CN Cl

TFA 281 244 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(1- isobutyrylazetidin-3- yl)benzonitrile³Et CN Cl

— 281 245 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2,2- dimethylpropanoyl)azetidin-3-yl]-3-ethoxybenzonitrile³ Et CN Cl

— 281 246 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1- (cyclopropylcarbonyl)azetidin-3-yl]-3-ethoxybenzonitrile³ Et CN Cl

— 281 248 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (methylsulfonyl)azetidin-3-yl]benzonitrile³ Et CN Cl

— 285 249 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (ethylsulfonyl)azetidin-3-yl]benzonitrile³ Et CN Cl

— 285 250 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (isopropylsulfonyl)azetidin-3-yl]benzonitrile³ Et CN Cl

— 285 251 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1- (cyclopropylsulfonyl)azetidin-3-yl]-3-ethoxybenzonitrile³ Et CN Cl

TFA 285 252 Methyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1- Et CN Cl

— 289 carboxylate³ 253 Ethyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1- Et CN Cl

— 289 carboxylate³ 254 Isopropyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1- Et CN Cl

— 289 carboxylate³ 255 3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N-(tert- butyl)azetidine-1-carboxamide³ Et CN Cl

— 292 256 3-{3-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}azetidine-1- carboxamide³ EtCN Cl

TFA 293 257 3-{3-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}-N-methylazetidine-1-carboxamide³ Et CN Cl

— 292 258 3-{3-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}-N-ethylazetidine-1-carboxamide³ Et CN Cl

— 292 259 3-{3-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}-N,N-dimethylazetidine-1-carboxamide³ Et CN Cl

— 296 260 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1- (2-hydroxyethyl)azetidin-3-yl]benzonitrile-d4³ Et CN Cl

— 219 263 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-(1- ethylazetidin-3-yl)-3- methoxybenzonitrile³ MeCN Cl

— 262 264 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-(1- isopropylazetidin-3-yl)-3- Me CN Cl

— 262 methoxybenzonitrile³ 265 4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-6-chloro-2-(1-isobutylazetidin-3-yl)-3- methoxybenzonitrile³ Me CN Cl

— 262 266 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1- (cyclopropylmethyl)azetidin-3-yl]-3-methoxybenzonitrile³ Me CN Cl

— 262 267 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-(1- cyclobutylazetidin-3-yl)-3-methoxybenzonitrile³ Me CN Cl

— 262 270 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2R)-2- hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile⁵ Me CN Cl

— 269 271 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxy- 2-methylpropyl)azetidin-3-yl]-3-methoxybenzonitrile³ Me CN Cl

— 269 274 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-(1- oxetan-3-ylazetidin-3-yl)benzonitrile³ Me CN Cl

— 262 275 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1- (tetrahydrofuran-3-yl)azetidin-3-yl]benzonitrile (from peak 1)⁵ Me CN Cl

— 272/273 276 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1- (tetrahydrofuran-3-yl)azetidin-3-yl]benzonitrile (from peak 2)⁵ Me CN Cl

— 272/273 277 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1- (tetrahydro-2H-pyran-4-yl)azetidin-3-yl]benzonitrile³ Me CN Cl

— 262 278 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1- (tetrahydrofuran-3-ylmethyl)azetidin-3-yl]benzonitrile (from peak 1)⁵ Me CN Cl

— 272/273 279 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1- (tetrahydrofuran-3-ylmethyl)azetidin-3-yl]benzonitrile (from peak 2)⁵ Me CN Cl

— 272/273 280 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1- (tetrahydro-2H-pyran-4-ylmethyl)azetidin-3-yl]benzonitrile³ Me CN Cl

— 262 282 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-(1- propionylazetidin-3-yl)benzonitrile³Me CN Cl

— 281 283 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-(1- isobutyrylazetidin-3-yl)-3-methoxybenzonitrile³ Me CN Cl

— 281 284 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1- (cyclopropylcarbonyl)azetidin-3-yl]-3-methoxybenzonitrile³ Me CN Cl

— 281 286 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1- (ethylsulfonyl)azetidin-3-yl]-3-methoxybenzonitrile³ Me CN Cl

— 285 287 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1- (isopropylsulfonyl)azetidin-3-yl]-3-methoxybenzonitrile³ Me CN Cl

— 285 288 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1- (cyclopropylsulfonyl)azetidin-3-yl]-3-methoxybenzonitrile³ Me CN Cl

— 285 290 Ethyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1- Me CN Cl

— 289 carboxylate³ 291 Isopropyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine- Me CN Cl

— 289 1-carboxylate³ 294 3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N- methylazetidine-1-carboxamide³ Me CN Cl

— 292 295 3-{3-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- methoxyphenyl}-N-ethylazetidine-1-carboxamide³ Me CN Cl

— 292 297 4-[1-(4-Amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2- hydroxyethyl)azetidin-3-yl]-3-methoxybenzonitrile-d4³ Me CN Cl

— 268 299 1-{1-[4,5-Dichloro-3-(1- isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4- Me Cl Cl

— 298 amine (peak 1)³ 300 2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5,6-dichloro-2-methoxyphenyl}azetidin-1- Me Cl Cl

— 298 and 219 yl)ethano (peak 1)³ 301 (2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-5,6- dichloro-2-methoxyphenyl}azetidin-1- yl)propan-2-ol (peak 1)⁵ Me Cl Cl

— 298 and 220 302 (2R)-1-(3-{3-[1-(4-Amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5,6- dichloro-2- methoxyphenyl}azetidin-1-yl)propan-2-ol (peak 1)⁵ Me Cl Cl

— 298 and 220 303 1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5,6-dichloro-2-methoxyphenyl}azetidin-1-yl)-2- methylpropan-2-ol (peak 2)³ Me Cl Cl

— 298 and 220 304 1-{1-[4,5-Dichloro-2-methoxy-3-(1-oxetan-3-ylazetidin-3- yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (peak 1)³ Me Cl Cl

— 298 and 213 305 (3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-5,6-dichloro-2-methoxyphenyl}azetidin-1- Me Cl Cl

— 298 and 219 yl)acetonitrile (peak 2)³ 3061-{1-[3-(1-Acetylazetidin-3-yl)- 4,5-dichloro-2-methoxyphenyl]ethyl}-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4- Me Cl Cl

— 298 and 281 amine (peak 2)³ ¹Synthesized according to the experimentalprocedure of compound listed; ³Compound isolated as a single enantiomer;⁵Compound isolated as a single diastereomer.

TABLE 5

Ex. No. Name R² R⁴ R⁵ R⁶ Salt Proc.¹ 308 4-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxyethyl)azetidin-3- Et CN Cl

— 307 and 219 yl]benzonitrile³ 309 4-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)ethyl]-6-chloro-3-ethoxy-2-{1-[(2S)-2-hydroxypropyl]azetidin-3- yl}benzonitrile⁵ Et CN Cl

— 220 and 219 ¹Synthesized according to the experimental procedure ofcompound listed; ³Compound isolated as a single enantiomer; ⁵Compoundisolated as a single diastereomer.Analytical Data

¹H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer,or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data(MS) for the compounds of Examples 214-218, 221-235, 238, 240-246,248-260, 263-267, 270, 271, 274-280, 282-284, 286-288, 290, 291, 294,295, 297, 299, 300-306, 308, and 309 is provided below in Table 6.

TABLE 6 MS Ex. No. [M + H]⁺ Solvent MHz ¹H NMR Spectra 214 440.2 DMSO-400 δ 8.11 (s, 1H), 7.48 (s, 1H), 6.23 (q, J = 7.0 Hz, 1H), d₆ 4.09-3.98(m, 1H), 3.93-3.84 (m, 2H), 3.84-3.75 (m, 1H), 3.74-3.65 (m, 1H),3.01-2.89 (m, 2H), 2.54 (s, 3H), 2.33 (q, J = 7.2 Hz, 2H), 1.71 (d, J =7.0 Hz, 3H), 1.33 (t, J = 6.9 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H). 215454.3 DMSO- 400 δ 8.11 (s, 1H), 7.49 (s, 1H), 6.23 (q, J = 7.0 Hz, 1H),d₆ 4.02-3.91 (m, 1H), 3.90-3.76 (m, 3H), 3.75-3.65 (m, 1H), 3.05-2.92(m, 2H), 2.54 (s, 3H), 2.25-2.14 (m, 1H), 1.71 (d, J = 7.0 Hz, 3H), 1.33(t, J = 6.9 Hz, 3H), 0.90-0.78 (m, 6H). 216 468.3 DMSO- 300 δ 8.11 (s,1H), 7.49 (s, 1H), 7.35 (br s, 2H), 6.22 (q, J = 7.0 Hz, d₆ 1H), 4.09(br s, 1H), 3.92 (brs, 2H), 3.83-3.76 (m, 1H), 3.75-3.65 (m, 1H), 3.01(br s, 2H), 2.54 (s, 3H), 2.16 (br s, 2H), 1.71 (d, J = 7.0 Hz, 3H),1.54 (br s, 1H), 1.32 (t, J = 6.9 Hz, 3H), 0.83 (d, J = 6.6 Hz, 6H). 217466.3 DMSO- 400 δ 8.11 (s, 1H), 7.48 (s, 1H), 6.23 (q, J = 7.0 Hz, 1H),d₆ 4.12-4.01 (m, 1H), 3.96-3.87 (m, 2H), 3.84-3.75 (m, 1H), 3.74-3.64(m, 1H), 3.08-2.96 (m, 2H), 2.54 (s, 3H), 2.20 (d, J = 6.7 Hz, 2H), 1.71(d, J = 7.1 Hz, 3H), 1.32 (t, J = 6.9 Hz, 3H), 0.77-0.66 (m, 1H),0.40-0.33 (m, 2H), 0.07-0.00 (m, 2H). 218 466.2 DMSO- 300 δ 8.11 (s,1H), 7.49 (s, 1H), 7.34 (br s, 2H), 6.22 (q, J = 6.9 Hz, d₆ 1H),4.10-3.95 (m, 1H), 3.85-3.61 (m, 4H), 3.13-2.92 (m, 3H), 2.54 (s, 3H),1.92-1.81 (m, 2H), 1.79-1.50 (m, 7H), 1.32 (t, J = 6.9 Hz, 3H). 221470.2 DMSO- 400 δ 8.11 (s, 1H), 7.48 (s, 1H), 6.23 (q, J = 7.1 Hz, 1H),4.35 (d, J = 4.5 Hz, d₆ 1H), 4.12-3.98 (m, 1H), 3.98-3.88 (m, 2H),3.84-3.74 (m, 1H), 3.73-3.64 (m, 1H), 3.61-3.51 (m, 1H), 3.07 (q, J =8.4 Hz, 2H), 2.54 (s, 3H), 2.28 (d, J = 5.9 Hz, 2H), 1.71 (d, J = 7.1Hz, 3H), 1.32 (t, J = 6.9 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). 222 484.3DMSO- 300 δ 8.11 (s, 1H), 7.48 (s, 1H), 7.35 (br s, 2H), 6.23 (q, J =6.9 Hz, d₆ 1H), 4.16-3.88 (m, 4H), 3.86-3.61 (m, 2H), 3.19-3.04 (m, 2H),2.54 (s, 3H), 2.26 (s, 2H), 1.71 (d, J = 7.0 Hz, 3H), 1.32 (t, J = 6.9Hz, 3H), 1.04 (s, 6H). 223 470.2 DMSO- 400 δ 8.11 (s, 1H), 7.48 (s, 1H),6.23 (q, J = 7.0 Hz, 1H), 4.44 (br s, d₆ 1H), 4.05-3.95 (m, 1H),3.94-3.89 (m, 1H), 3.88-3.82 (m, 1H), 3.82-3.75 (m, 1H), 3.74-3.65 (m,1H), 3.17-3.07 (m, 2H), 3.07-2.99 (m, 1H), 2.55 (s, 3H), 2.20-2.13 (m,1H), 1.71 (d, J = 7.0 Hz, 3H), 1.37-1.29 (m, 3H), 0.86-0.78 (m, 3H). 224470.2 DMSO- 400 δ 8.11 (s, 1H), 7.49 (s, 1H), 6.23 (q, J = 6.6 Hz, 1H),4.43 (br s, d₆ 1H), 4.05-3.90 (m, 2H), 3.87-3.75 (m, 2H), 3.73-3.64 (m,1H), 3.16-3.02 (m, 3H), 2.54 (s, 3H), 2.23-2.11 (m, 1H), 1.71 (d, J =6.9 Hz, 3H), 1.37-1.29 (m, 3H), 0.86-0.79 (m, 3H). 225 470.2 DMSO- 400 δ8.11 (s, 1H), 7.48 (s, 1H), 6.23 (q, J = 7.0 Hz, 1H), d₆ 4.12-4.01 (m,2H), 3.95-3.84 (m, 2H), 3.83-3.74 (m, 1H), 3.74-3.64 (m, 1H), 3.31-3.26(m, 3H), 3.20 (s, 3H), 3.13-3.02 (m, 2H), 2.54 (s, 3H), 1.71 (d, J = 7.0Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H). 226 514.2 DMSO- 400 δ 8.11 (s, 1H),7.50 (s, 1H), 7.33 (br s, 2H), 6.23 (q, J = 7.0 Hz, d₆ 1H), 4.08-3.98(m, 1H), 3.91-3.82 (m, 2H), 3.82-3.74 (m, 1H), 3.74-3.64 (m, 1H),3.28-3.15 (m, 12H), 2.54 (s, 3H), 1.71 (d, J = 7.0 Hz, 3H), 1.32 (t, J =6.9 Hz, 3H). 227 482.2 DMSO- 300 δ 8.11 (s, 1H), 7.48 (s, 1H), 7.33 (brs, 2H), 6.23 (q, J = 7.0 Hz, d₆ 1H), 4.11-3.97 (m, 1H), 3.94-3.77 (m,3H), 3.76-3.58 (m, 3H), 3.56-3.43 (m, 2H), 3.10-2.97 (m, 2H), 2.96-2.87(m, 1H), 2.55 (s, 3H), 1.71 (d, J = 7.0 Hz, 3H), 1.67-1.56 (m, 2H), 1.34(t, J = 6.9 Hz, 3H). 228 482.3 DMSO- 300 δ 8.11 (s, 1H), 7.50 (s, 1H),7.36 (br s, 2H), 6.23 (q, J = 6.9 Hz, d₆ 1H), 4.11-3.97 (m, 1H),3.93-3.57 (m, 6H), 3.56-3.40 (m, 2H), 3.12-3.04 (m, 1H), 3.03-2.96 (m,1H), 2.95-2.87 (m, 1H), 2.54 (s, 3H), 1.79-1.56 (m, 5H), 1.34 (t, J =6.9 Hz, 3H). 229 496.3 DMSO- 300 δ 8.11 (s, 1H), 7.49 (s, 1H), 7.34 (brs, 2H), 6.23 (q, J = 6.9 Hz, d₆ 1H), 4.14-3.95 (m, 1H), 3.94-3.63 (m,6H), 3.29-3.17 (m, 2H), 3.12-2.96 (m, 2H), 2.55 (s, 3H), 2.23-2.09 (m,1H), 1.71 (d, J = 7.0 Hz, 3H), 1.65-1.52 (m, 2H), 1.33 (t, J = 6.9 Hz,3H), 1.19-1.08 (m, 2H). 230 496.2 DMSO- 300 δ 8.11 (s, 1H), 7.48 (s,1H), 7.36 (br s, 2H), 6.22 (q, J = 6.8 Hz, d₆ 1H), 4.16-3.99 (m, 1H),3.98-3.51 (m, 7H), 3.30-3.24 (m, 1H), 3.10-2.98 (m, 2H), 2.54 (s, 3H),2.33 (d, J = 7.4 Hz, 2H), 2.21-2.09 (m, 1H), 1.97-1.83 (m, 1H), 1.71 (d,J = 7.0 Hz, 3H), 1.52-1.37 (m, 1H), 1.33 (t, J = 6.9 Hz, 3H). 231 496.3DMSO- 300 δ 8.11 (s, 1H), 7.48 (s, 1H), 7.35 (br s, 2H), 6.22 (q, J =6.7 Hz, d₆ 1H), 4.14-4.00 (m, 1H), 3.96-3.86 (m, 2H), 3.84-3.52 (m, 5H),3.29-3.22 (m, 1H), 3.12-2.96 (m, 2H), 2.54 (s, 3H), 2.33 (d, J = 7.3 Hz,2H), 2.22-2.09 (m, 1H), 1.99-1.83 (m, 1H), 1.71 (d, J = 7.0 Hz, 3H),1.53-1.38 (m, 1H), 1.33 (t, J = 6.8 Hz, 3H). 232 510.3 DMSO- 300 δ 8.11(s, 1H), 7.48 (s, 1H), 7.35 (br s, 2H), 6.22 (q, J = 7.0 Hz, d₆ 1H),4.15-4.00 (m, 1H), 3.96-3.84 (m, 2H), 3.83-3.73 (m, 3H), 3.72-3.62 (m,1H), 3.30-3.18 (m, 2H), 3.08-2.94 (m, 2H), 2.54 (s, 3H), 2.22 (d, J =6.3 Hz, 2H), 1.71 (d, J = 7.0 Hz, 3H), 1.55 (d, J = 11.7 Hz, 3H), 1.32(t, J = 6.9 Hz, 3H), 1.17-1.01 (m, 2H). 233 494.1 DMSO- 400 δ 8.11 (s,1H), 7.50 (s, 1H), 7.29 (br s, 2H), 6.23 (q, J = 7.0 Hz, d₆ 1H),4.26-4.15 (m, 1H), 4.03-3.94 (m, 2H), 3.86-3.65 (m, 2H), 3.42 (q, J =9.1 Hz, 2H), 3.20 (q, J = 10.2 Hz, 2H), 2.55 (s, 3H), 1.71 (d, J = 7.1Hz, 3H), 1.33 (t, J = 6.9 Hz, 3H). 234 508.2 DMSO- 400 δ 8.11 (s, 1H),7.49 (s, 1H), 7.35 (br s, 2H), 6.23 (q, J = 6.9 Hz, d₆ 1H), 4.13-4.02(m, 1H), 3.98-3.87 (m, 2H), 3.84-3.75 (m, 1H), 3.74-3.65 (m, 1H),3.13-3.03 (m, 2H), 2.61-2.51 (m, 5H), 2.38-2.23 (m, 2H), 1.71 (d, J =7.0 Hz, 3H), 1.33 (t, J = 6.9 Hz, 3H). 235 451.1 DMSO- 400 δ 8.11 (s,1H), 7.52 (s, 1H), 7.31 (br s, 2H), 6.23 (q, J = 7.0 Hz, d₆ 1H),4.22-4.11 (m, 1H), 3.91 (q, J = 6.8 Hz, 2H), 3.84-3.74 (m, 1H),3.72-3.61 (m, 3H), 3.32-3.21 (m, 2H), 2.54 (s, 3H), 1.72 (d, J = 7.0 Hz,3H), 1.31 (t, J = 6.9 Hz, 3H). 238 526.2 DMSO- 400 δ 8.11 (s, 1H), 7.47(s, 1H), 6.22 (q, J = 7.0 Hz, 1H), d₆ 4.09-3.95 (m, 3H), 3.85-3.75 (m,3H), 3.74-3.64 (m, 1H), 3.53-3.41 (m, 2H), 2.54 (s, 3H), 1.71 (d, J =7.1 Hz, 3H), 1.31 (t, J = 7.0 Hz, 3H), 1.10 (s, 6H), 0.95 (t, J = 7.1Hz, 3H). 240 511.3 DMSO- 400 δ 8.11 (s, 1H), 7.77 (q, J = 4.4 Hz, 1H),7.51 (s, 1H), 6.23 (q, J = 7.0 Hz, d₆ 1H), 4.08-3.98 (m, 1H), 3.85-3.75(m, 1H), 3.74-3.62 (m, 3H), 3.38-3.34 (m, 1H), 3.31-3.27 (m, 1H), 2.57(d, J = 4.7 Hz, 3H), 2.54 (s, 3H), 1.71 (d, J = 7.1 Hz, 3H), 1.32 (t, J= 7.0 Hz, 3H), 1.02 (s, 6H). 241 511.3 DMSO- 400 δ 8.11 (s, 1H), 7.53(s, 1H), 7.01 (s, 2H), 6.26 (q, J = 7.0 Hz, d₆ 1H), 4.12-4.00 (m, 1H),3.88-3.79 (m, 2H), 3.69-3.62 (m, 2H), 3.48-3.35 (m, 2H), 3.15 (br s,6H), 2.57 (s, 3H), 1.76 (d, J = 7.1 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H),1.15 (d, J = 1.7 Hz, 6H). 242 454.2 DMSO- 400 δ 8.11 (s, 1H), 7.54 (d, J= 2.1 Hz, 1H), 7.33 (br s, 2H), 6.25 (q, d₆ J = 7.0 Hz, 1H), 4.57-4.35(m, 3H), 4.28-4.19 (m, 1H), 4.18-4.08 (m, 1H), 3.85-3.74 (m, 2H), 2.55(s, 3H), 1.76 (d, J = 2.3 Hz, 3H), 1.72 (d, J = 7.0 Hz, 3H), 1.37 (t, J= 6.9 Hz, 3H). 243 468.2 DMSO- 300 δ 8.28 (s, 1H), 7.59 (s, 1H), 6.28(q, J = 6.9 Hz, 1H), d₆ 4.58-4.35 (m, 3H), 4.31-4.06 (m, 2H), 3.88-3.70(m, 2H), 2.57 (s, 3H), 2.12-1.99 (m, 2H), 1.75 (d, J = 7.0 Hz, 3H), 1.38(t, J = 6.9 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H). 244 482.3 DMSO- 300 δ8.11 (s, 1H), 7.54 (s, 1H), 7.34 (br s, 2H), 6.25 (q, J = 6.9 Hz, d₆1H), 4.62-4.36 (m, 3H), 4.30-4.06 (m, 2H), 3.87-3.74 (m, 2H), 2.55 (s,3H), 2.46-2.39 (m, 1H), 1.72 (d, J = 7.0 Hz, 3H), 1.38 (t, J = 6.9 Hz,3H), 1.01-0.92 (m, 6H). 245 496.1 DMSO- 300 δ 8.11 (s, 1H), 7.54 (s,1H), 6.25 (q, J = 6.9 Hz, 1H), 4.70 (br s, d₆ 2H), 4.50-4.36 (m, 1H),4.22 (br s, 2H), 3.86-3.74 (m, 2H), 2.54 (s, 3H), 1.72 (d, J = 7.1 Hz,3H), 1.38 (t, J = 6.9 Hz, 3H), 1.11 (s, 9H). 246 480.2 DMSO- 300 δ 8.12(s, 1H), 7.55 (d, J = 3.1 Hz, 1H), 7.36 (br s, 2H), 6.25 (q, d₆ J = 7.0Hz, 1H), 4.72-4.62 (m, 1H), 4.61-4.42 (m, 2H), 4.31-4.10 (m, 2H),3.87-3.74 (m, 2H), 2.55 (s, 3H), 1.73 (d, J = 7.0 Hz, 3H), 1.61-1.48 (m,1H), 1.38 (t, J = 6.9 Hz, 3H), 0.76-0.63 (m, 4H). 248 490.1 DMSO- 300 δ8.12 (s, 1H), 7.57 (s, 1H), 7.35 (br s, 2H), 6.24 (q, J = 6.9 Hz, d₆1H), 4.54-4.39 (m, 1H), 4.25-4.11 (m, 4H), 3.88-3.65 (m, 2H), 3.01 (s,3H), 2.55 (s, 3H), 1.73 (d, J = 7.1 Hz, 3H), 1.34 (t, J = 6.9 Hz, 3H).249 504.2 DMSO- 300 δ 8.11 (s, 1H), 7.55 (s, 1H), 7.35 (br s, 2H), 6.23(q, J = 6.7 Hz, d₆ 1H), 4.56-4.38 (m, 1H), 4.29-4.10 (m, 4H), 3.88-3.65(m, 2H), 3.15 (q, J = 7.4 Hz, 2H), 2.55 (s, 3H), 1.73 (d, J = 7.0 Hz,3H), 1.34 (t, J = 6.9 Hz, 3H), 1.20 (t, J = 7.3 Hz, 3H). 250 518.2 DMSO-300 δ 8.11 (s, 1H), 7.55 (s, 1H), 7.35 (br s, 2H), 6.23 (q, J = 6.9 Hz,d₆ 1H), 4.55-4.40 (m, 1H), 4.26-4.10 (m, 4H), 3.88-3.65 (m, 2H),3.31-3.26 (m, 1H), 2.54 (s, 3H), 1.73 (d, J = 7.0 Hz, 3H), 1.34 (t, J =6.9 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H). 251 516.2 DMSO- 300 δ 8.27 (s,1H), 7.61 (s, 1H), 6.27 (q, J = 6.9 Hz, 1H), d₆ 4.58-4.42 (m, 1H),4.31-4.13 (m, 4H), 3.90-3.64 (m, 2H), 2.84-2.69 (m, 1H), 2.57 (s, 3H),1.75 (d, J = 7.0 Hz, 3H), 1.34 (t, J = 6.9 Hz, 3H), 1.01-0.96 (m, 2H),0.93-0.88 (m, 2H). 252 470.1 DMSO- 300 δ 8.11 (s, 1H), 7.53 (s, 1H),7.34 (br s, 2H), 6.24 (q, J = 7.0 Hz, d₆ 1H), 4.52-4.37 (m, 1H),4.35-4.19 (m, 4H), 3.79 (q, J = 6.8 Hz, 2H), 3.55 (s, 3H), 2.54 (s, 3H),1.72 (d, J = 7.0 Hz, 3H), 1.37 (t, J = 6.9 Hz, 3H). 253 484.2 DMSO- 300δ 8.11 (s, 1H), 7.53 (s, 1H), 7.34 (br s, 2H), 6.24 (q, J = 7.0 Hz, d₆1H), 4.52-4.37 (m, 1H), 4.35-4.17 (m, 4H), 4.00 (q, J = 7.1 Hz, 2H),3.79 (q, J = 6.9 Hz, 2H), 2.54 (s, 3H), 1.72 (d, J = 7.0 Hz, 3H), 1.37(t, J = 6.9 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). 254 498.3 DMSO- 300 δ8.27 (s, 1H), 7.58 (s, 1H), 6.27 (q, J = 6.8 Hz, 1H), d₆ 4.80-4.66 (m,1H), 4.49-4.35 (m, 1H), 4.33-4.14 (m, 4H), 3.87-3.69 (m, 2H), 2.57 (s,3H), 1.74 (d, J = 7.0 Hz, 3H), 1.37 (t, J = 6.9 Hz, 3H), 1.15 (d, J =6.2 Hz, 6H). 255 511.3 DMSO- 300 δ 8.11 (s, 1H), 7.52 (s, 1H), 7.31 (brs, 2H), 6.24 (q, J = 7.0 Hz, d₆ 1H), 5.84 (s, 1H), 4.35-4.24 (m, 1H),4.24-4.15 (m, 2H), 4.07-3.94 (m, 2H), 3.83-3.68 (m, 2H), 2.55 (s, 3H),1.72 (d, J = 7.0 Hz, 3H), 1.36 (t, J = 6.9 Hz, 3H), 1.21 (s, 9H). 256455.2 DMSO- 400 δ 8.15 (s, 1H), 7.53 (s, 1H), 6.25 (q, J = 7.0 Hz, 1H),5.96 (br s, d₆ 2H), 4.40-4.30 (m, 1H), 4.24-4.16 (m, 2H), 4.15-4.01 (m,2H), 3.85-3.68 (m, 2H), 2.55 (s, 3H), 1.73 (d, J = 7.0 Hz, 3H), 1.36 (t,J = 6.9 Hz, 3H). 257 469.2 DMSO- 300 δ 8.11 (s, 1H), 7.51 (s, 1H), 7.35(br s, 2H), 6.37 (q, J = 4.2 Hz, d₆ 1H), 6.24 (q, J = 7.0 Hz, 1H),4.43-4.29 (m, 1H), 4.24-4.15 (m, 2H), 4.13-3.99 (m, 2H), 3.85-3.68 (m,2H), 2.54 (s, 3H), 2.51 (d, J = 4.7 Hz, 3H), 1.72 (d, J = 7.0 Hz, 3H),1.36 (t, J = 6.9 Hz, 3H). 258 483.2 DMSO- 300 δ 8.11 (s, 1H), 7.51 (s,1H), 7.35 (br s, 2H), 6.44 (t, J = 5.6 Hz, d₆ 1H), 6.24 (q, J = 6.9 Hz,1H), 4.43-4.28 (m, 1H), 4.26-4.14 (m, 2H), 4.12-3.98 (m, 2H), 3.86-3.67(m, 2H), 3.04-2.92 (m, 2H), 2.54 (s, 3H), 1.72 (d, J = 7.0 Hz, 3H), 1.36(t, J = 6.9 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). 259 483.2 DMSO- 400 δ8.11 (s, 1H), 7.52 (s, 1H), 6.24 (q, J = 6.9 Hz, 1H), d₆ 4.42-4.32 (m,1H), 4.31-4.24 (m, 2H), 4.22-4.12 (m, 2H), 3.85-3.71 (m, 2H), 2.76 (s,6H), 2.55 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H).260 460.2 DMSO- 400 δ 8.11 (s, 1H), 7.48 (s, 1H), 6.23 (q, J = 7.0 Hz,1H), 4.35 (s, d₆ 1H), 4.11-4.01 (m, 1H), 3.95-3.87 (m, 2H), 3.84-3.74(m, 1H), 3.74-3.64 (m, 1H), 3.12-3.01 (m, 2H), 2.55 (s, 3H), 1.71 (d, J= 7.1 Hz, 3H), 1.33 (t, J = 6.9 Hz, 3H). 263 426.2 DMSO- 300 δ 8.11 (s,1H), 7.46 (s, 1H), 7.38 (br s, 2H), 6.24 (q, J = 7.0 Hz, d₆ 1H),4.11-3.97 (m, 1H), 3.95-3.84 (m, 2H), 3.64 (s, 3H), 3.00-2.88 (m, 2H),2.55 (s, 3H), 2.39-2.27 (m, 2H), 1.72 (d, J = 7.1 Hz, 3H), 0.86 (t, J =7.1 Hz, 3H). 264 440.2 DMSO- 400 δ 8.11 (s, 1H), 7.47 (s, 1H), 6.28-6.19(m, 1H), d₆ 4.02-3.92 (m, 1H), 3.91-3.82 (m, 2H), 3.64 (s, 3H),3.03-2.89 (m, 2H), 2.55 (s, 3H), 2.24-2.14 (m, 1H), 1.72 (d, J = 6.9 Hz,3H), 0.84 (d, J = 5.9 Hz, 6H). 265 454.2 DMSO- 300 δ 8.11 (s, 1H), 7.46(s, 1H), 7.34 (br s, 2H), 6.23 (q, J = 7.0 Hz, d₆ 1H), 4.14-4.01 (m,1H), 3.96-3.84 (m, 2H), 3.64 (s, 3H), 3.04-2.92 (m, 2H), 2.55 (s, 3H),2.13 (d, J = 6.9 Hz, 2H), 1.72 (d, J = 7.1 Hz, 3H), 1.60-1.45 (m, 1H),0.83 (d, J = 6.6 Hz, 6H). 266 452.2 DMSO- 300 δ 8.11 (s, 1H), 7.46 (s,1H), 7.37 (br s, 2H), 6.24 (q, J = 7.0 Hz, d₆ 1H), 4.15-4.00 (m, 1H),3.98-3.87 (m, 2H), 3.64 (s, 3H), 3.06-2.95 (m, 2H), 2.55 (s, 3H),2.28-2.12 (m, 2H), 1.72 (d, J = 7.1 Hz, 3H), 0.78-0.64 (m, 1H),0.42-0.32 (m, 2H), 0.08-−0.01 (m, 2H). 267 452.2 DMSO- 300 δ 8.11 (s,1H), 7.47 (s, 1H), 7.38 (br s, 2H), 6.23 (q, J = 6.9 Hz, d₆ 1H),4.10-3.95 (m, 1H), 3.83-3.70 (m, 2H), 3.63 (s, 3H), 3.10-2.92 (m, 3H),2.54 (s, 3H), 1.92-1.79 (m, 2H), 1.78-1.50 (m, 7H). 270 456.2 DMSO- 300δ 8.11 (s, 1H), 7.46 (s, 1H), 7.34 (br s, 2H), 6.24 (q, J = 7.0 Hz, d₆1H), 4.36 (d, J = 4.5 Hz, 1H), 4.13-4.00 (m, 1H), 3.99-3.87 (m, 2H),3.63 (s, 3H), 3.61-3.52 (m, 1H), 3.11-3.01 (m, 2H), 2.55 (s, 3H), 2.28(d, J = 5.4 Hz, 2H), 1.72 (d, J = 7.1 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H).271 470.3 DMSO- 300 δ 8.11 (s, 1H), 7.46 (s, 1H), 7.33 (br s, 2H), 6.23(q, J = 7.0 Hz, d₆ 1H), 4.16-3.91 (m, 4H), 3.63 (s, 3H), 3.17-3.05 (m,2H), 2.55 (s, 3H), 2.26 (s, 2H), 1.72 (d, J = 7.1 Hz, 3H), 1.04 (s, 6H).274 454.1 DMSO- 300 δ 8.11 (s, 1H), 7.48 (s, 1H), 7.35 (br s, 2H), 6.24(q, J = 7.0 Hz, d₆ 1H), 4.55-4.48 (m, 2H), 4.37-4.29 (m, 2H), 4.21-4.07(m, 1H), 3.93-3.83 (m, 2H), 3.69-3.58 (m, 4H), 3.24-3.12 (m, 2H), 2.55(s, 3H), 1.72 (d, J = 7.1 Hz, 3H). 275 468.2 DMSO- 300 δ 8.11 (s, 1H),7.47 (s, 1H), 7.35 (br s, 2H), 6.24 (q, J = 7.1 Hz, d₆ 1H), 4.11-3.97(m, 1H), 3.95-3.82 (m, 2H), 3.75-3.58 (m, 6H), 3.56-3.41 (m, 2H),3.08-2.97 (m, 2H), 2.94-2.87 (m, 1H), 2.55 (s, 3H), 1.72 (d, J = 7.1 Hz,3H), 1.68-1.56 (m, 1H). 276 468.2 DMSO- 300 δ 8.11 (s, 1H), 7.48 (s,1H), 7.35 (br s, 2H), 6.24 (q, J = 6.9 Hz, d₆ 1H), 4.11-3.98 (m, 1H),3.94-3.83 (m, 2H), 3.74-3.58 (m, 6H), 3.52 (dd, J = 8.9, 5.1 Hz, 1H),3.44 (dd, J = 8.9, 2.5 Hz, 1H), 3.11-2.95 (m, 2H), 2.95-2.86 (m, 1H),2.55 (s, 3H), 1.72 (d, J = 7.0 Hz, 3H), 1.67-1.56 (m, 1H). 277 482.2DMSO- 300 δ 8.11 (s, 1H), 7.47 (s, 1H), 7.37 (br s, 2H), 6.24 (q, J =6.9 Hz, d₆ 1H), 4.12-3.98 (m, 1H), 3.94-3.83 (m, 2H), 3.83-3.73 (m, 2H),3.65 (s, 3H), 3.29-3.18 (m, 2H), 3.09-2.96 (m, 2H), 2.55 (s, 3H),2.21-2.10 (m, 1H), 1.72 (d, J = 7.0 Hz, 3H), 1.64-1.53 (m, 2H),1.24-1.08 (m, 2H). 278 482.2 DMSO- 300 δ 8.11 (s, 1H), 7.47 (s, 1H),7.37 (br s, 2H), 6.23 (q, J = 7.0 Hz, d₆ 1H), 4.14-3.99 (m, 1H),3.98-3.85 (m, 2H), 3.75-3.52 (m, 6H), 3.29 (dd, J = 8.3, 6.4 Hz, 1H),3.09-2.95 (m, 2H), 2.55 (s, 3H), 2.36-2.29 (m, 2H), 2.23-2.07 (m, 1H),1.96-1.83 (m, 1H), 1.72 (d, J = 7.1 Hz, 3H), 1.52-1.37 (m, 1H). 279482.2 DMSO- 300 δ 8.11 (s, 1H), 7.47 (s, 1H), 7.38 (br s, 2H), 6.23 (q,J = 6.9 Hz, d₆ 1H), 4.14-3.99 (m, 1H), 3.96-3.85 (m, 2H), 3.75-3.51 (m,6H), 3.32-3.26 (m, 1H), 3.09-2.98 (m, 2H), 2.55 (s, 3H), 2.35-2.30 (m,2H), 2.23-2.08 (m, 1H), 1.97-1.83 (m, 1H), 1.72 (d, J = 7.1 Hz, 3H),1.54-1.35 (m, 1H). 280 496.2 DMSO- 300 δ 8.11 (s, 1H), 7.46 (s, 1H),7.36 (br s, 2H), 6.23 (q, J = 7.0 Hz, d₆ 1H), 4.14-4.00 (m, 1H),3.96-3.86 (m, 2H), 3.83-3.74 (m, 2H), 3.64 (s, 3H), 3.29-3.19 (m, 2H),3.05-2.94 (m, 2H), 2.55 (s, 3H), 2.20 (d, J = 6.3 Hz, 2H), 1.72 (d, J =7.0 Hz, 3H), 1.59-1.45 (m, 3H), 1.17-1.01 (m, 2H). 282 454.1 DMSO- 300 δ8.11 (s, 1H), 7.52 (s, 1H), 7.35 (br s, 2H), 6.26 (q, J = 6.9 Hz, d₆1H), 4.58-4.37 (m, 3H), 4.31-4.21 (m, 1H), 4.19-4.09 (m, 1H), 3.71 (d, J= 3.3 Hz, 3H), 2.55 (s, 3H), 2.11-2.00 (m, 2H), 1.73 (d, J = 7.1 Hz,3H), 0.95 (t, J = 7.5 Hz, 3H). 283 468.2 DMSO- 300 δ 8.11 (s, 1H), 7.52(s, 1H), 7.35 (br s, 2H), 6.26 (q, J = 7.0 Hz, d₆ 1H), 4.64-4.37 (m,3H), 4.31-4.19 (m, 1H), 4.19-4.08 (m, 1H), 3.72 (d, J = 3.9 Hz, 3H),2.55 (s, 3H), 2.46-2.39 (m, 1H), 1.73 (d, J = 7.0 Hz, 3H), 1.02-0.92 (m,6H). 284 466.2 DMSO- 300 δ 8.12 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.35(br s, 2H), 6.26 (q, d₆ J = 7.0 Hz, 1H), 4.73-4.62 (m, 1H), 4.61-4.42(m, 2H), 4.31-4.22 (m, 1H), 4.22-4.11 (m, 1H), 3.73 (d, J = 2.3 Hz, 3H),2.56 (s, 3H), 1.74 (d, J = 7.0 Hz, 3H), 1.55 (d, J = 5.6 Hz, 1H),0.74-0.64 (m, 4H). 286 490.1 DMSO- 300 δ 8.11 (s, 1H), 7.54 (s, 1H),7.35 (br s, 2H), 6.24 (q, J = 7.0 Hz, d₆ 1H), 4.54-4.40 (m, 1H),4.25-4.13 (m, 4H), 3.67 (s, 3H), 3.19-3.10 (m, 2H), 2.55 (s, 3H), 1.73(d, J = 7.1 Hz, 3H), 1.24-1.17 (m, 3H). 287 504.2 DMSO- 300 δ 8.11 (s,1H), 7.53 (s, 1H), 7.39 (br s, 2H), 6.24 (q, J = 7.0 Hz, d₆ 1H),4.55-4.40 (m, 1H), 4.23-4.15 (m, 4H), 3.68 (s, 3H), 3.30-3.22 (m, 1H),2.55 (s, 3H), 1.74 (d, J = 7.1 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H). 288502.1 DMSO- 300 δ 8.12 (s, 1H), 7.55 (s, 1H), 7.42 (br s, 2H), 6.25 (q,J = 7.0 Hz, d₆ 1H), 4.56-4.42 (m, 1H), 4.29-4.17 (m, 4H), 3.68 (s, 3H),2.83-2.72 (m, 1H), 2.55 (s, 3H), 1.74 (d, J = 7.0 Hz, 3H), 1.03-0.95 (m,2H), 0.93-0.88 (m, 2H). 290 470.2 DMSO- 300 δ 8.11 (s, 1H), 7.51 (s,1H), 7.35 (br s, 2H), 6.25 (q, J = 6.9 Hz, d₆ 1H), 4.52-4.37 (m, 1H),4.36-4.16 (m, 4H), 4.00 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 2.55 (s, 3H),1.73 (d, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). 291 484.2 DMSO- 300δ 8.11 (s, 1H), 7.52 (s, 1H), 7.35 (br s, 2H), 6.25 (q, J = 7.0 Hz, d₆1H), 4.81-4.66 (m, 1H), 4.52-4.36 (m, 1H), 4.25 (d, J = 8.4 Hz, 4H),3.70 (s, 3H), 2.55 (s, 3H), 1.73 (d, J = 7.1 Hz, 3H), 1.16 (d, J = 6.3Hz, 6H). 294 455.1 DMSO- 300 δ 8.11 (s, 1H), 7.49 (s, 1H), 7.36 (br s,2H), 6.36 (q, J = 4.4 Hz, d₆ 1H), 6.25 (q, J = 7.0 Hz, 1H), 4.44-4.30(m, 1H), 4.25-4.14 (m, 2H), 4.13-3.99 (m, 2H), 3.69 (s, 3H), 2.55 (s,3H), 2.51 (d, J = 4.6 Hz, 3H), 1.73 (d, J = 7.0 Hz, 3H). 295 469.1 DMSO-300 δ 8.11 (s, 1H), 7.49 (s, 1H), 7.33 (br s, 2H), 6.44 (t, J = 5.5 Hz,d₆ 1H), 6.25 (q, J = 7.0 Hz, 1H), 4.44-4.30 (m, 1H), 4.26-4.15 (m, 2H),4.12-3.99 (m, 2H), 3.69 (s, 3H), 3.03-2.92 (m, 2H), 2.55 (s, 3H), 1.73(d, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). 297 469.1 DMSO- 300 δ8.11 (s, 1H), 7.46 (s, 1H), 7.37 (br s, 2H), 6.24 (q, J = 7.0 Hz, d₆1H), 4.35 (s, 1H), 4.14-3.99 (m, 1H), 3.99-3.86 (m, 2H), 3.64 (s, 3H),3.11-3.00 (m, 2H), 2.55 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H). 299 449.0DMSO- 300 δ 8.11 (s, 1H), 7.46 (s, 1H), 6.21 (q, J = 7.0 Hz, 1H), d₆3.99-3.84 (m, 2H), 3.84-3.69 (m, 1H), 3.57 (s, 3H), 2.97-2.87 (m, 1H),2.85-2.75 (m, 1H), 2.55 (s, 3H), 2.14-2.07 (m, 1H), 1.70 (d, J = 7.1 Hz,3H), 0.85 (d, J = 5.9 Hz, 6H). 300 451.2 DMSO- 300 δ 8.11 (s, 1H), 7.48(s, 1H), 7.32 (br s, 2H), 6.21 (q, J = 7.0 Hz, d₆ 1H), 4.56 (br s, 1H),4.12-3.89 (m, 3H), 3.58 (s, 3H), 3.46-3.36 (m, 2H), 3.28-3.04 (m, 2H),2.55 (s, 3H), 1.71 (d, J = 7.1 Hz, 3H). 301 465.0 — 302 465.0 — 303479.1 DMSO- 300 δ 8.11 (s, 1H), 7.48 (s, 1H), 7.32 (br s, 2H), 6.21 (q,J = 7.0 Hz, d₆ 1H), 4.45-3.83 (m, 4H), 3.58 (s, 3H), 2.55 (s, 3H),2.45-2.28 (m, 2H), 1.71 (d, J = 7.0 Hz, 3H), 1.06 (s, 6H). 304 463.0DMSO- 300 δ 8.11 (s, 1H), 7.46 (s, 1H), 7.33 (br s, 2H), 6.21 (q, J =7.0 Hz, d₆ 1H), 4.54-4.46 (m, 2H), 4.35-4.27 (m, 2H), 4.01-3.80 (m, 3H),3.62-3.53 (m, 4H), 3.14-3.06 (m, 1H), 3.03-2.93 (m, 1H), 2.54 (s, 3H),1.70 (d, J = 7.1 Hz, 3H). 305 446.1 DMSO- 300 δ 8.11 (s, 1H), 7.49 (s,1H), 7.32 (br s, 2H), 6.22 (q, J = 6.9 Hz, d₆ 1H), 4.04-3.84 (m, 3H),3.62 (s, 2H), 3.57 (s, 3H), 3.28-3.21 (m, 1H), 3.17-3.08 (m, 1H), 2.55(s, 3H), 1.71 (d, J = 7.0 Hz, 3H). 306 449.1 DMSO- 300 δ 8.11 (s, 1H),7.51 (s, 1H), 7.32 (br s, 2H), 6.22 (q, J = 7.0 Hz, d₆ 1H), 4.55-4.41(m, 2H), 4.40-4.29 (m, 1H), 4.26-4.14 (m, 1H), 4.11-4.02 (m, 1H), 3.65(d, J = 3.3 Hz, 3H), 2.55 (s, 3H), 1.78-1.75 (m, 3H), 1.72 (d, J = 6.2Hz, 3H). 308 455.3 DMSO- 300 δ 7.95 (s, 1H), 7.19 (s, 1H), 7.17-7.13 (m,1H), 6.58 (s, 2H), d₆ 6.11 (q, J = 7.1 Hz, 1H), 4.41 (t, J = 5.4 Hz,1H), 4.13-3.99 (m, 1H), 3.97-3.86 (m, 2H), 3.84-3.67 (m, 2H), 3.13-3.00(m, 2H), 2.41 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 1.69 (d, J = 7.1 Hz,3H), 1.30 (t, J = 6.9 Hz, 3H). 309 469.2 DMSO- 300 δ 7.95 (s, 1H), 7.18(s, 1H), 7.16-7.13 (m, 1H), 6.58 (s, 2H), d₆ 6.11 (q, J = 7.0 Hz, 1H),4.36 (d, J = 4.5 Hz, 1H), 4.15-4.00 (m, 1H), 3.99-3.87 (m, 2H),3.84-3.67 (m, 2H), 3.63-3.50 (m, 1H), 3.18-2.99 (m, 2H), 2.36 (s, 3H),2.28 (d, J = 5.9 Hz, 2H), 1.69 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 6.9 Hz,3H), 1.00 (d, J = 6.2 Hz, 3H).

Example 313.5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N,N-dimethylpyridine-2-carboxamide

Step 1: 5-Bromo-N,N-dimethylpyridine-2-carboxamide

5-Bromopyridine-2-carboxylic acid (20 g, 100 mmol, Frontier Scientificcatalog #B1704) was stirred in methylene chloride (30 mL) and cooled to0° C. 2.0 M oxalyl chloride in methylene chloride (100 mL) was addedslowly, followed by N,N-dimethylformamide (0.8 mL). The mixture wasstirred for 30 minutes at 0° C. and then room temperature overnight. Themixture was evaporated, redissolved in methylene chloride (130 mL) andwas added slowly to a mixture of dimethylamine hydrochloride (9.8 g, 120mmol) and triethylamine (56.1 mL, 400 mmol) in methylene chloride (130mL) cooled to 0° C. The reaction mixture was stirred at room temperaturefor 2 hrs. This mixture was diluted with methylene chloride (200 mL) andwashed with saturated sodium bicarbonate, brine, dried over sodiumsulfate, filtered and evaporated. The product was purified by FCC onsilica gel using ethyl acetate in hexanes (0-60%) gradient to give5-bromo-N,N-dimethylpyridine-2-carboxamide, (22.0 g, 100%). LCMScalculated for C₈H₁₀BrN₂O (M+H)⁺: m/z=229.0, 231.0; found: 228.9, 230.9.

Step 2: {6-[(Dimethylamino)carbonyl]pyridin-3-yl}boronic acid

A mixture of 5-bromo-N,N-dimethylpyridine-2-carboxamide (23 g, 98 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (27 g,110 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (Aldrich, Catalog No. 379670) (1:1) (4.8 g,5.9 mmol), 1,1′-bis(diphenylphosphino)ferrocene (Aldrich, Catalog No.177261) (3.3 g, 5.9 mmol), and potassium acetate (30 g, 300 mmol) in1,4-dioxane (600 mL) was degassed with nitrogen and was heated at 120°C. for 16 hrs. The mixture was cooled to room temperature and dilutedwith ethyl acetate (600 mL) and water (600 mL). The aqueous layer wasconcentrated in vacuo to give a solid residue. The solids were taken upin acetonitrile and filtered to remove the residual insoluble salts. Theacetonitrile was removed in vacuo to give{6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (12 g, 60%). LCMScalculated for C₇H₁₂BN₂O₃ (M+H)⁺: m/z=195.1; found: 195.1.

Step 3. 4-Acetyl-2-bromo-6-chloro-3-methoxybenzonitrile

1-(3-Bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (2.0 g, 7.5 mmol,Example 43, Step 1) was combined with potassium cyanide (0.58 g, 9.0mmol) in N,N-dimethylformamide (16 mL) and heated to 85° C. in an oilbath. After heating for 18 hrs, the reaction was allowed to cool to roomtemperature and iodomethane (0.90 mL, 11 mmol) and potassium carbonate(2.1 g, 15 mmol) were added. The reaction was heated to 65° C. andmonitored by LC/MS. After heating for 3 hrs the reaction was completeand allowed to cool to room temperature, then taken up in ethyl acetateand washed with water, brine, and dried over magnesium sulfate. Theresultant solution was concentrated to give the crude product as a darkoil. The product was purified by FCC on silica gel eluting hexane: ethylacetate gradient to give 4-acetyl-2-bromo-6-chloro-3-methoxybenzonitrile(1.65 g, 75%) as a solid residue. LCMS calculated for C₁₀H₈BrClNO₂(M+H)⁺: m/z=287.9, 289.9; found: 288.1, 290.0.

Step 4:5-(3-Acetyl-5-chloro-6-cyano-2-methoxyphenyl)-N,N-dimethylpyridine-2-carboxamide

Sodium carbonate (3.0 g, 20 mmol) in water (20 mL) was added to amixture 4-acetyl-2-bromo-6-chloro-3-methoxybenzonitrile (2.5 g, 8.7mmol) and {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (1.9 g,10. mmol, Example 301 Step 2) in acetonitrile (100 mL). The reaction wasdegassed with N₂ and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (400 mg, 0.4 mmol) was added and the reactionmixture was degassed again with N₂. The reaction was heated at 100° C.for 4 hrs and was complete by LC/MS. The reaction was allowed to cool toroom temperature and was partitioned between water and EtOAc. Thecombined organic layer was washed with brine, dried over MgSO₄,filtered, concentrated to give the crude product. The product waspurified by FCC on silica gel eluting a hexane: ethyl acetate gradientto give5-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)-N,N-dimethylpyridine-2-carboxamideas yellow oil (2.2 g, 71%). LCMS calculated for C₁₈H₁₇ClN₃O₃ (M+H)⁺:m/z=358.1; found: 358.1.

Step 5:5-[3-Chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide

Sodium tetrahydroborate (320 mg, 8.4 mmol) was added to a mixture of5-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)-N,N-dimethylpyridine-2-carboxamide(2 g, 6 mmol) in methanol (100 mL) cooled at 0° C. The reaction wasstirred at 0° C. for 1 h, quenched with water and partitioned betweenwater and EtOAc. The combined organic layer was washed with brine, driedover MgSO₄, filtered and concentrated to give crude5-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamideas clear oil (2.0 g, 100%). LCMS calculated for C₁₈H₁₉ClN₃O₃ (M+H)⁺:m/z=360.1; found: 360.1.

Step 6:5-[3-Chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide

Thionyl chloride (800 μL, 10 mmol) was added dropwise to a solution of5-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide(2 g, 6 mmol), methylene chloride (100 mL) and N,N-dimethylformamide(100 μL) at room temperature. The reaction was stirred for 5 hrs and wascomplete by LC/MS. The reaction mixture was partitioned between EtOAcand water. The combined organic layer was washed with saturated NaHCO₃,brine, dried over Na₂SO₄, filtered and concentrated to give crude5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamideas an oil (1.8 g, 80%). LCMS calculated for C₁₈H₁₈Cl₂N₃O₂ (M+H)⁺:m/z=378.1; found: 378.1.

Step 7:5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N,N-dimethylpyridine-2-carboxamide

Cesium carbonate (3000 mg, 10 mmol) was added to a mixture of3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1100 mg, 7.1 mmol) and5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide(1.8 g, 4.8 mmol) in N,N-dimethylformamide (50 mL). The reaction wasstirred at 80° C. for 3 hrs and was allowed to cool to room temperature.The reaction was diluted with EtOAc, washed with water, brine, driedover Na₂SO₄, filtered and concentrated to give the crude product. Thiswas purified by FCC on silica gel eluting (hexanes/10% EtOH in EtOAc,0-100%) gradient to give the title compound as light yellow oil (2.0 g,80%). LCMS calculated for C₂₄H₂₄ClN₈O₂ (M+H)⁺: m/z=491.1; found: 491.2.¹H NMR (400 MHz, CD₃OD) δ 8.74 (d, J=1.4 Hz, 1H), 8.15 (d, J=2.2 Hz,1H), 8.13 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 6.43 (q, J=7.0Hz, 1H), 3.32 (s, 3H), 3.16 (s, 3H), 3.07 (s, 3H), 2.64 (s, 3H), 1.89(d, J=7.1 Hz, 3H).

The enantiomers were separated by Chiral column HPLC using: PhenomenexLux-Cellulose 1 column, 21.1×250 mm, 5 micron particle size 15% ethanolin hexanes 18 mL/min˜5 mg/injection to give the following: First peakretention time: 2.09 min,5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N,N-dimethylpyridine-2-carboxamide;Second peak retention time: 3.92 min,5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N,N-dimethylpyridine-2-carboxamide.

Example 314.5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Step 1: 4-Acetyl-5-hydroxy-2-methylbenzonitrile

The 1-(4-bromo-2-hydroxy-5-methylphenyl)ethanone (8.5 g, 37 mmol, AlfaAesar catalog #H29125) was combined with zinc cyanide (8.7 g, 74 mmol)in N,N-dimethylformamide (75 mL) degassed with nitrogen and thetris(dibenzylideneacetone)dipalladium(0) (Aldrich Catalog No. 328774)(1.0 g, 1.1 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (AldrichCatalog No. 526460) (1.5 g, 2.6 mmol) were added. The reaction wasdegassed again with nitrogen and heated to 120° C. and monitored byLC/MS. After heating for 18 hrs the reaction was complete, the reactionwas allowed to cool to room temperature, taken up in ethyl acetate andwashed with water (2×), brine, dried over magnesium sulfate andconcentrated to give the crude product as a dark amber oil. The productwas purified by FCC on silica gel eluting hexane: ethyl acetate gradientto give 4-acetyl-5-hydroxy-2-methylbenzonitrile as a solid (6.3 g, 98%).LCMS calculated for C₁₀H₁₀NO₂ (M+H)⁺: m/z=176.1; found: 176.2.

Step 2: 4-Acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile

The 4-acetyl-5-hydroxy-2-methylbenzonitrile (6.7 g, 38 mmol) wasdissolved in acetic acid (80 mL) and the N-iodosuccinimide (10. g, 46mmol) was added. The reaction was heated to 80° C. in an oil bath andmonitored by LC/MS. After heating for 4 hrs the reaction was complete.This was allowed to cool and was concentrated in vacuo to give a darkoil. The oil was taken up in ethyl acetate and washed with water, sodiumbicarbonate (3×, until remained slightly basic), brine, dried overmagnesium sulfate and concentrated to give the crude product as a darkoil. The product was purified by FCC on silica gel eluting hexane: ethylacetate gradient to give 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrileas pale yellow solid (7.2 g, 62%). LCMS calculated for C₁₀H₉INO₂ (M+H)⁺:m/z=301.9; found: 301.9.

Step 3: 4-Acetyl-2-iodo-3-ethoxy-6-methylbenzonitrile

The 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile (5.0 g, 17 mmol) wasdissolved in N,N-dimethylformamide (50.0 mL) and the potassium carbonate(4.6 g, 33 mmol) and ethyl iodide (2.1 mL, 33 mmol) were added. Thereaction was heated to 60° C. and monitored by LC/MS. After heating for2 hrs the reaction was complete. This was allowed to cool, diluted withethyl acetate (300 mL) and filtered to remove the remaining solids. Theorganic layer was washed with water (3×), brine, dried over magnesiumsulfate and concentrated to give the crude product as a dark solid. Theproduct was purified by FCC on silica gel eluting hexane: ethyl acetategradient to give 4-acetyl-3-ethoxy-2-iodo-6-methylbenzonitrile as a paleyellow crystalline solid (5.0 g, 96%). LCMS calculated for C₁₂H₁₃INO₂(M+H)⁺: m/z=329.9; found: 330.0.

Step 4:5-(3-Acetyl-6-cyano-2-ethoxy-5-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

Sodium carbonate (3 g, 30 mmol) in water (20 mL) was added to a mixtureof 4-acetyl-3-ethoxy-2-iodo-6-methylbenzonitrile (3 g, 9 mmol) and{6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (1700 mg, 8.8mmol, Example 313, Step 2) in acetonitrile (100 mL). The mixture wasdegassed with nitrogen and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (400 mg, 0.4 mmol) was added. The reactionwas degassed again with nitrogen and was heated to 100° C. for 4 hrs.The reaction was allowed to cool to room temperature, diluted with waterand extracted with EtOAc. The combined organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated to give the crudeproduct. The product was purified by FCC on silica gel eluting(hexane/EtOAc, 0-100%) gradient to give5-(3-acetyl-6-cyano-2-ethoxy-5-methylphenyl)-N,N-dimethylpyridine-2-carboxamideproduct as yellow solid (2.3 g, 75%). LCMS calculated for C₂₀H₂₂N₃O₃(M+H)⁺: m/z=352.1; found: 352.2.

Step 5:5-[2-Cyano-6-ethoxy-5-(1-hydroxyethyl)-3-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Sodium tetrahydroborate (370 mg, 9.8 mmol) was added to a mixture of5-(3-acetyl-6-cyano-2-ethoxy-5-methylphenyl)-N,N-dimethylpyridine-2-carboxamide(2.3 g, 6.5 mmol) in methanol (100 mL) at 0° C. The reaction was stirredat 0° C. for 1 h. The reaction was partitioned between water and EtOAc.The combined organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to give the crude product5-[2-cyano-6-ethoxy-5-(1-hydroxyethyl)-3-methylphenyl]-N,N-dimethylpyridine-2-carboxamideas a clear oil (2.3 g, 99%). LCMS calculated for C₂₀H₂₄N₃O₃ (M+H)⁺:m/z=354.1; found: 354.2.

Step 6:5-[3-(1-Chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Thionyl chloride (900 μL, 10 mmol) was added dropwise to a solution of5-[2-cyano-6-ethoxy-5-(1-hydroxyethyl)-3-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(2.3 g, 6.5 mmol) in methylene chloride (100 mL) andN,N-dimethylformamide (100 μL) at room temperature. The reaction wasstirred for 3 hrs, was diluted with methylene chloride (100 mL) andwashed with water saturated NaHCO₃. The combined organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated to givecrude5-[3-(1-chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(2.2 g, 91%). LCMS calculated for C₂₀H₂₃ClN₃O₂ (M+H)⁺: m/z=372.1; found:372.2.

Step 7:5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Cesium carbonate (4000 mg, 10 mmol) was added to a mixture of3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1300 mg, 8.5 mmol) and5-[3-(1-chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(2.1 g, 5.6 mmol) in N,N-dimethylformamide (100 mL). The reaction wasstirred at 80° C. for 3 hrs and monitored by LC/MS. The reaction mixturewas diluted with EtOAc, washed with water, brine, dried over Na₂SO₄,filtered and concentrated to give the crude product. The product waspurified by FCC on silica gel eluting (hexane/10% EtOH in EtOAc,gradient 0-100%) gradient to give the title compound (2.1 g, 77%). LCMScalculated for C₂₆H₂₉N₈O₂ (M+H)⁺: m/z=485.2; found: 485.2. ¹H NMR (500MHz, DMSO-d₆) δ 8.70-8.63 (m, 1H), 8.10 (s, 1H), 8.06 (dd, J=8.0, 2.2Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.51 (s, 1H), 6.34 (q, J=7.0 Hz, 1H),3.59-3.47 (m, 1H), 3.33 (m, 1H), 3.03 (s, 3H), 2.96 (s, 3H), 2.57 (s,3H), 2.45 (s, 3H), 1.79 (d, J=7.1 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H). Theenantiomers were separated by Chiral column HPLC using: AD column 20×25cm, eluting hexane; 30% ethanol @ 13 mL/min˜5 mg/injection to give:First peak retention time: 1.63 minutes,5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;Second peak retention time: 4.13 minutes,5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide.

Example 315.4-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxy-6-methylbenzonitrile

Step 1: 4-Acetyl-5-hydroxy-2-methylbenzonitrile

The 1-(4-bromo-2-hydroxy-5-methylphenyl)ethanone (8.5 g, 37 mmol, AlfaAesar catalog #H29125) was combined with zinc cyanide (8.7 g, 74 mmol)in N,N-dimethylformamide (75 mL) degassed with nitrogen and thetris(dibenzylideneacetone)dipalladium(0) (1.0 g, 1.1 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.5 g, 2.6mmol) were added. The reaction was degassed again with nitrogen andheated to 120° C. and monitored by LC/MS. After heating for 18 h, thereaction was complete, the reaction was allowed to cool to roomtemperature, taken up in ethyl acetate and washed with water (2×),brine, dried over magnesium sulfate and concentrated to give the crudeproduct as a dark amber oil. The product was purified by FCC on silicagel eluting hexane: ethyl acetate gradient to give4-acetyl-5-hydroxy-2-methylbenzonitrile as a solid (6.3 g, 98%). LCMScalculated for C₁₀H₁₀NO₂ (M+H)⁺: m/z=176.1; found: 176.2.

Step 2: 4-Acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile

The 4-acetyl-5-hydroxy-2-methylbenzonitrile (6.7 g, 38 mmol) wasdissolved in acetic acid (80 mL) and the N-Iodosuccinimide (10. g, 46mmol) was added. The reaction was heated to 80° C. in an oil bath andmonitored by LC/MS. After heating for 4 hrs the reaction was complete.This was allowed to cool and was concentrated in vacuo to give a darkoil. The oil was taken up in ethyl acetate and washed with water, sodiumbicarbonate (3×, until remained slightly basic), brine, dried overmagnesium sulfate and concentrated to give the crude product as a darkoil. The product was purified by FCC on silica gel eluting hexane: ethylacetate gradient to give 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrileas pale yellow solid (7.2 g, 62%). LCMS calculated for C₁₀H₉INO₂ (M+H)⁺:m/z=301.9; found: 301.9.

Step 3: 4-Acetyl-2-iodo-3-methoxy-6-methylbenzonitrile

The 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile (5.0 g, 17 mmol) wasdissolved in N,N-dimethylformamide (50 mL) and the potassium carbonate(4.6 g, 33 mmol) and methyl iodide (2.1 mL, 33 mmol) were added. Thereaction was heated to 60° C. and monitored by LC/MS. After heating for2 hrs the reaction was complete. This was allowed to cool, diluted withethyl acetate (300 mL) and filtered to remove the remaining solids. Theorganic layer was washed with water (3×), brine, dried over magnesiumsulfate and concentrated to give the crude product as a dark solid. Theproduct was purified by FCC on silica gel eluting hexane: ethyl acetategradient to give 4-acetyl-3-methoxy-2-iodo-6-methylbenzonitrile as apale yellow crystalline solid (5.0 g, 96%). LCMS calculated forC₁₁H₁₁INO₂ (M+H)⁺: m/z=315.9; found: 316.0.

Step 4: tert-butyl3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate

Zinc (1.70 g, 26.0 mmol) and celite (oven dried, 500 mg) were groundtogether in a flask until the solids appeared homogenous, the flask washeated with a heat gun while under high-vac for 5 minutes and thenback-filled with nitrogen. The solids were suspended inN,N-dimethylacetamide (4.2 mL) and 1,2-dibromoethane (0.13 mL, 1.5 mmol)was added. The reaction mixture was heated at 70° C. for 30 min and thencooled to room temperature. Chlorotrimethylsilane (0.16 mL, 1.3 mmol)was added dropwise and stirring was continued for 2 hrs at roomtemperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate(2.70 g, 9.52 mmol) in N,N-dimethylacetamide (4.35 mL) was then addedslowly and the resulting mixture was heated at 50° C. for 2 hrs. Thezinc-iodo reagent was allowed to cool to room temperature and was takenup in a syringe and filtered through a PTFE filter (adapted with aneedle) directly into a suspension oftris(dibenzylideneacetone)dipalladium(0) (0.111 g, 0.121 mmol) andtri-(2-furyl)phosphine (0.056 g, 0.24 mmol) and4-acetyl-2-iodo-3-methoxy-6-methylbenzonitrile (2.0 g, 6.3 mmol) inN,N-dimethylacetamide (19.6 mL) pre-degassed by bubbling N₂. Thereaction mixture was degassed with nitrogen again and heated to 70° C.After heating for 30 minutes the reaction was complete by LC/MS. Thiswas allowed to cool, taken up in ethyl acetate and washed with water,brine, dried over magnesium sulfate and concentrated to give the crudeproduct as an oil. The product was purified by FCC on silica gel elutinghexane; ethyl acetate gradient to give tert-butyl3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate asa clear oil. (1.8 g, 82%). LCMS calculated for C₁₅H₁₇N₂O₄ (M+H)⁺:m/z=289.1; found: 289.1.

Step 5: tert-butyl3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate

The tert-butyl3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate(2.2 g, 6.4 mmol) was dissolved in methanol (20 mL) and cooled in icebath. The sodium tetrahydroborate (0.26 g, 7.0 mmol) was addedportionwise and the reaction was monitored by LC/MS. After stirring for1 h the reaction was complete. This was diluted with ethyl acetate andwater. The combined organic layer was washed with water, saturatedsodium bicarbonate, brine, dried over magnesium sulfate and concentratedto give crude tert-butyl3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylateas a yellow foam (2.1 g, 99%). LCMS calculated for C₁₅H₁₉N₂O₄ (M+H)⁺:m/z=291.1; found: 291.1.

Step 6: tert-butyl3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate

The tert-butyl3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate(2.1 g, 6.4 mmol) was taken up in methylene chloride (50.0 mL) andN,N-dimethylformamide (0.59 mL), cooled in an ice bath and the thionylchloride (0.56 mL, 7.7 mmol) was added slowly. After stirring for 2 hrsthe reaction was complete by LC/MS and was partitioned between ethylacetate and water. The combined organic layer was washed with watersaturated sodium bicarbonate, brine, dried over magnesium sulfate andconcentrated to give crude tert-butyl3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylateas an oil (2.2 g, 100%). LCMS calculated for C₁₅H₁₈ClN₂O₃ (M+H)⁺:m/z=309.1; found: 309.1.

Step 7: tert-butyl3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate

The tert-butyl3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate(2.3 g, 6.3 mmol) was dissolved in N,N-dimethylformamide (68 mL) withcesium carbonate (4.1 g, 13 mmol) and3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.4 g, 9.4 mmol) and washeated in an oil bath to 80° C. The reaction was stirred for 18 hrs andallowed to cool to room temperature. The reaction mixture was taken upin ethyl acetate, filtered, washed with water, brine, dried overmagnesium sulfate and concentrated to give the crude product. Theproduct was purified by FCC on silica gel eluting a (hexane: 10% ethanolethyl acetate) gradient to give tert-butyl3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylateas a semisolid (1.5 g, 50%). LCMS calculated for C₂₅H₃₂N₇O₃ (M+H)⁺:m/z=478.2; found: 478.2. The enantiomers were separated by Chiral columnHPLC using: Phenomenex LUX Cellulose Column, 21.1×250 mm, 5 micron, 15%ethanol in hexane, 18 mL/min˜5 mg/injection to give: First peakretention time: 2.1 minutes, tert-butyl3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate;Second peak retention time: 3.9 minutes, tert-butyl3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate.

Step 8:4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-methoxy-6-methylbenzonitrilebis(trifluoroacetate)

The tert-butyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate(0.35 g, 0.73 mmol) (Step 7, peak 1) was dissolved in methylene chloride(3.0 mL) and trifluoroacetic acid (1.0 mL) at room temperature. Afterstirring for 1 h the reaction was complete by LC/MS. The reaction wasconcentrated in vacuo to give4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-methoxy-6-methylbenzonitrile(bis(trifluoroacetate) as a viscous amber oil (0.50 g, 100%). LCMScalculated for C₂₀H₂₄N₇O (M+H)⁺: m/z=378.2; found: 378.2.

Step 9:4-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxy-6-methylbenzonitrile

The4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-methoxy-6-methylbenzonitrilebis(trifluoroacetate) (0.074 g, 0.10 mmol) was dissolved in ethanol (3.0mL) and DIPEA (0.071 mL, 0.41 mmol) and the (S)-(−)-methyloxirane(0.0071 g, 0.12 mmol) was added. The reaction was heated in a sealedtube to 90° C. and monitored by LC/MS. After heating for 6 hrs thereaction was purified without workup by prep HPLC on a C-18 columneluting water: acetonitrile gradient buffered pH 10 to give the titlecompound as a white amorphous solid (0.018 g, 40%). The product wasisolated as a single enantiomer. LCMS calculated for C₂₃H₃₀N₇O₂ (M+H)⁺:m/z=436.2; found: 436.3. ¹H NMR (300 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.21(s, 1H), 6.22 (q, J=7.1 Hz, 1H), 4.34 (d, J=4.5 Hz, 1H), 4.09-3.83 (m,3H), 3.60 (s, 3H), 3.58-3.51 (m, 1H), 3.12-2.95 (m, 2H), 2.55 (s, 3H),2.33 (s, 3H), 2.27 (d, J=5.9 Hz, 2H), 1.71 (d, J=7.1 Hz, 3H), 1.00 (d,J=6.2 Hz, 3H).

Example 316.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]benzonitrile

Step 1. 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide

N,O-dimethylhydroxylamine hydrochloride (500 mg, 5 mmol) was added to amixture of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1400 mg, 3.7 mmol), N,N-diisopropylethylamine (1000μL, 7 mmol) and 5-bromopyridine-2-carboxylic acid (500 mg, 2 mmol,Frontier Scientific catalog #B1704) in N,N-dimethylformamide (10 mL).The reaction mixture was stirred overnight at room temperature and wascomplete by LC/MS. The reaction was partitioned between water and EtOAc.The combined organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to give the crude product. The product waspurified on by FCC on silica gel eluting a hexane: EtOAc (0-30%)gradient to give 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide clearoil (0.50 g, 60%). LCMS calculated for C₈H₁₀BrN₂O₂ (M+H)⁺: m/z=244.9,246.9; found: 244.9, 246.9.

Step 2. 1-(5-bromopyridin-2-yl)ethanone

Methylmagnesium chloride 3.0 M in THF (0.5 mL) was added dropwise to amixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (200 mg, 0.8mmol) in tetrahydrofuran (10 mL) at 0° C. After stirring for 1 hr atroom temperature, the reaction was quenched with 1 N NH₄Cl and wasextracted with EtOAc. The combined organic layer was washed with brineand dried over MgSO₄, concentrated to give the crude product1-(5-bromopyridin-2-yl)ethanone (0.15 g, 90%). LCMS calculated forC₇H₇BrNO (M+H)⁺: m/z=199.9, 201.9; found: 199.9, 201.9.

Step 3. 2-(5-bromopyridin-2-yl)propan-2-ol

Methylmagnesium chloride 3.0 M in THF (0.3 mL) was added dropwise to amixture of 1-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) intetrahydrofuran (10 mL) at 0° C. After stirring for 1 h at roomtemperature, the reaction was quenched with 1 N NH₄Cl and was extractedwith EtOAc. The combined organic layer was washed with brine and driedover MgSO₄, concentrated to give crude2-(5-bromopyridin-2-yl)propan-2-ol (0.1 g, 100%). LCMS calculated forC₈H₁₁BrNO (M+H)⁺: m/z=215.9, 217.9; found: 215.8, 217.8.

Step 4. [6-(1-hydroxy-1-methylethyl)pyridin-3-yl]boronic acid

A mixture of 2-(5-bromopyridin-2-yl)propan-2-ol (70 mg, 0.3 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (90. mg,0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (10 mg, 0.01 mmol), and potassiumacetate (100 mg, 1 mmol) in 1,4-dioxane (5 mL) was heated at 120° C.overnight. The reaction was complete by LC/MS, was concentrated in vacuoto give crude [6-(1-hydroxy-1-methylethyl)pyridin-3-yl]boronic acid.LCMS calculated for C₈H₁₃BNO₃ (M+H)⁺: m/z=182.1; found: 182.1.

Step 5.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]benzonitrilebis(2,2,2-trifluoroacetate)

Sodium carbonate (10 mg, 0.09 mmol) in water (0.5 mL) was added to amixture of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile(20 mg, 0.04 mmol, racemic intermediate from Example 43, Step 5) and[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]boronic acid (12 mg, 0.069mmol, Example 306, Step 4) in acetonitrile (1 mL). The reaction mixturewas degassed with N₂ and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (2 mg, 0.002 mmol) was added. The reactionwas degassed with N₂ again and heated to 100° C. for 1 h. The reactionwas allowed to cool to room temperature and was purified without workupby prep HPLC on a C-18 column eluting a water; acetonitrile gradientbuffered with TFA to give the title compound as white amorphous solid.The product was isolated as a racemic mixture. LCMS calculated forC₂₅H₂₇ClN₇O₂ (M+H)⁺: m/z=492.1; found: 492.1. ¹H NMR (500 MHz, DMSO-d₆)δ 8.60 (d, J=2.0 Hz, 1H), 8.22 (s, 1H), 7.96 (dd, J=8.2, 2.3 Hz, 1H),7.80 (d, J=8.3 Hz, 1H), 7.73 (s, 1H), 6.36 (q, J=7.0 Hz, 1H), 3.52-3.40(m, 1H), 3.40-3.30 (m, 1H), 2.59 (s, 3H), 1.80 (d, J=7.0 Hz, 3H), 1.48(d, J=2.3 Hz, 6H), 0.88 (t, J=7.0 Hz, 3H).

Example 317.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-methoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile

Using procedures analogous to Example 314, but using methyl iodideinstead of ethyl iodide in Step 3,4-acetyl-2-iodo-3-methoxy-6-methylbenzonitrile was prepared and using3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineinstead of {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid(racemic intermediate from Step 4), the title compound4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-methoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrilewas prepared. The product was isolated as a racemic mixture. LCMScalculated for C₂₃H₂₄N₇O₃S (M+H)⁺: m/z=478.1; found: 478.2. ¹H NMR (300MHz, CD₃OD) δ 9.24 (d, J=2.2 Hz, 1H), 9.03 (d, J=2.0 Hz, 1H), 8.59 (t,J=2.1 Hz, 1H), 8.31 (s, 1H), 7.68 (s, 1H), 6.56 (q, J=7.1 Hz, 1H), 3.38(s, 3H), 3.31 (s, 3H), 2.72 (s, 3H), 2.59 (s, 3H), 1.98 (d, J=7.1 Hz,3H).

Example 318.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile

Step 1. 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile

The 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile was prepared byanalogous methods described in Example 43, Step 1 and Step 2, but usingN-iodosuccinimide. LCMS calculated for C₁₁H₁₀ClINO₂ (M+H)⁺: m/z=349.9;found: 350.0.

Step 2. 4-acetyl-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile

The 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (0.20 g, 0.57 mmol)was combined with pyrrolidine (0.052 mL, 0.63 mmol) inN,N-dimethylformamide (2.0 mL) with cesium carbonate (0.19 g, 0.57 mmol)and heated to 120° C. in a sealed tube. After heating for 18 hrs thereaction was allowed to cool, taken up in ethyl acetate, washed withwater, brine, dried over magnesium sulfate and concentrated to give thecrude product as a dark oil. The product was purified by FCC on silicagel eluting with hexane: ethyl acetate gradient to give4-acetyl-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile as an oil(0.045 g, 27%). LCMS calculated for C₁₅H₁₈ClN₂O₂ (M+H)⁺: m/z=293.1;found 293.1.

Step 3.6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-pyrrolidin-1-ylbenzonitrile

The 4-acetyl-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile (0.045 g,0.15 mmol) was dissolved in methanol (3 mL) and cooled in an ice bath.The sodium tetrahydroborate (0.0058 g, 0.15 mmol) was added and thereaction was monitored by LC/MS. After stirring for 1 h, the reactionwas taken up in ethyl acetate and washed with water, sodium bicarbonate,brine and dried over magnesium sulfate to give crude6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-pyrrolidin-1-ylbenzonitrile as aclear oil (0.045 g, 100%). LCMS calculated for C₁₅H₂₀ClN₂O₂ (M+H)⁺:m/z=295.1; found 295.1.

Step 4.6-chloro-4-(1-chloroethyl)-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile

The 6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-pyrrolidin-1-ylbenzonitrile(0.045 g, 0.15 mmol) was taken up in methylene chloride (3.0 mL) andN,N-dimethylformamide (0.002 mL, 0.03 mmol) and cooled in an ice bath.The thionyl chloride (0.017 mL, 0.23 mmol) was added and the reactionwas monitored by LC/MS. After stirring for 2 hrs the reaction wascomplete. The reaction was then taken up in ethyl acetate, washed withsodium bicarbonate, brine, dried over magnesium sulfate and concentratedto give crude6-chloro-4-(1-chloroethyl)-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile as ayellow oil (0.048 g, 100%). LCMS calculated for C₁₅H₁₉Cl₂N₂O (M+H)⁺:m/z=313.1; found 313.1.

Step 5.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile

The 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile(0.048 g, 0.15 mmol, racemic mixture) was combined with3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.034 g, 0.23 mmol) andcesium carbonate (0.10 g, 0.31 mmol) in N,N-dimethylformamide (3.0 mL)and heated in an oil bath to 85° C. After heating for 18 hrs thereaction was complete. The crude reaction was purified with out work upby prep HPLC on a C-18 column eluting water: acetonitrile gradientbuffered pH 10 to give the title compound as a white amorphous solid(0.012 g, 18%). The product was isolated as a racemic mixture. LCMScalculated for C₂₁H₂₅ClN₇O (M+H)⁺: m/z=426.1; found 426.1. ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (s, 1H), 6.91 (s, 1H), 6.25 (q, J=7.1 Hz, 1H), 3.71(dp, J=15.7, 8.1, 7.2 Hz, 4H), 3.49-3.35 (m, 2H), 2.55 (s, 3H),2.00-1.76 (m, 4H), 1.70 (d, J=7.1 Hz, 3H), 1.34 (t, J=7.0 Hz, 3H).

Example 319.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile

Step 1.4-acetyl-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile

To a mixture of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (50 mg,0.1 mmol, Example 318, Step 1), 3-methoxyazetidine hydrochloride (21 mg,0.17 mmol Chem-Impex catalog #20140) and cesium carbonate (70. mg, 0.21mmol) in 1,4-dioxane (4 mL) was added(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.07mmol) and tris(dibenzylideneacetone)dipalladium (0) (60 mg, 0.07 mmol).The reaction mixture was degassed with N₂. The reaction was heated at80° C. for 2 hrs and was monitored by LC/MS. The reaction was allowed tocool to room temperature, was diluted with water and extracted withEtOAc. The combined organic layers were washed with brine, dried overMgSO4, filtered and concentrated to give the crude product. The productwas purified by FCC on silica gel eluting (hexanes: EtOAc 0-70%)gradient to give to4-acetyl-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile asclear oil (0.030 g, 70%). LCMS calculated for C₁₅H₁₈ClN₂O₃ (M+H)⁺:m/z=309.1; found: 309.1.

Step 2.6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(3-methoxyazetidin-1-yl)benzonitrile

4-Acetyl-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile (30mg, 0.1 mmol was dissolved in methanol (5 mL) cooled to 0° C. and sodiumtetrahydroborate (5.5 mg, 0.14 mmol) was added. Reaction was stirred for1 h at 0° C. The reaction was partitioned between EtOAc and water. Thecombined organic layer was washed with water and saturated NaHCO₃,brine, dried over Na₂SO₄, filtered and concentrated to give crude6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(3-methoxyazetidin-1-yl)benzonitrile(0.030 g, 100%). LCMS calculated for C₁₅H₂₀ClN₂O₃ (M+H)⁺: m/z=311.1;found: 311.1.

Step 3.6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile

6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(3-methoxyazetidin-1-yl)benzonitrile(30 mg, 0.1 mmol) (racemic mixture) was dissolved in methylene chloride(5 mL) and N,N-dimethylformamide (100 μL, 1 mmol). Thionyl chloride (18μL, 0.24 mmol) was added dropwise at room temperature and the reactionwas stirred for 2 hrs. The reaction was diluted with EtOAc, washed withwater and saturated NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated to give the crude6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile(0.030 g, 100%). LCMS calculated for C₁₅H₁₉Cl₂N₂O₃ (M+H)⁺: m/z=329.1;found: 329.1.

Step 4.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile

Cesium carbonate (50 mg, 0.2 mmol) was added to a mixture of3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (16 mg, 0.10 mmol) and6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile(30 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) and thereaction was stirred at 80° C. overnight. The mixture was diluted withEtOAc, washed with water, brine, dried over Na₂SO₄, filtered andconcentrated the crude product. The product was purified was purified byprep HPLC on a C-18 column eluting water: acetonitrile gradient bufferedpH 10 to give the title compound as a white amorphous solid (0.007 g,20%). The product was isolated as a racemic mixture. LCMS calculated forC₂₁H₂₅ClN₇O₂ (M+H)⁺: m/z=442.1; found: 442.1. ¹H NMR (400 MHz, DMSO-d₆)δ 8.11 (s, 1H), 6.80 (s, 1H), 6.18 (d, J=7.1 Hz, 1H), 4.58-4.44 (m, 2H),4.18 (m, 1H), 4.13-4.01 (m, 2H), 3.81-3.62 (m, 2H), 3.23 (s, 3H), 2.55(s, 3H), 1.69 (d, J=7.1 Hz, 3H), 1.35 (t, J=7.0 Hz, 3H).

Example 320.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-(1-isopropylazetidin-3-yl)-6-methylbenzonitrile

Step 1:4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-ethoxy-6-methylbenzonitrilebis(trifluoroacetate)

Using methods described in Example 315 but using ethyl iodide in Step 3,instead of methyl iodide, the intermediate4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-ethoxy-6-methylbenzonitrilebis(trifluoroacetate) was prepared. LCMS calculated for C₂₁H₂₆N₇O(M+H)⁺: m/z=392.2; found: 392.2.

Step 2.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-(1-isopropylazetidin-3-yl)-6-methylbenzonitrile

To a mixture of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-ethoxy-6-methylbenzonitrile(70 mg, 0.2 mmol) in methanol (50 mL) was added acetone (0.1 mL, 2 mmol)and sodium cyanoborohydride (17 mg, 0.27 mmol). The reaction was stirredat room temperature for 1 h, and was complete by LC/MS. The reaction wasquenched with water and was extracted with EtOAc. The combined organiclayer was washed with brine, dried over MgSO₄, filtered and concentratedto give the crude product. The product was purified by prep HPLC on aC-18 column eluting water: acetonitrile gradient buffered pH 10 to givethe title compound as a white amorphous solid (0.030 g, 40%). Theproduct was isolated as a racemic mixture. LCMS calculated for C₂₄H₃₂N₇O(M+H)⁺: m/z=434.2; found: 434.3. ¹H NMR (300 MHz, CD₃OD) δ 8.17 (s, 1H),7.35 (s, 1H), 6.37 (q, J=7.1 Hz, 1H), 4.17-3.98 (m, 4H), 3.90-3.71 (m,3H), 2.65 (s, 3H), 2.46 (s, 4H), 1.84 (d, J=7.1 Hz, 3H), 1.42 (t, J=7.0Hz, 3H), 1.03 (dd, J=6.2, 1.4 Hz, 6H).

Example 321.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-[1-(2-hydroxy-2-methylpropyl)azetidin-3-yl]-6-methylbenzonitrile

The4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-ethoxy-6-methylbenzonitrile(0.055 g, 0.14 mmol, chiral intermediate from Example 320, Step 1) wascombined with tetrahydrofuran (22 mL), DIPEA (0.049 mL, 0.28 mmol) andoxirane, 2,2-dimethyl- (0.018 mL, 0.21 mmol) at room temperature. Thereaction was heated to 95° C. and allowed to stir overnight. Thereaction was allowed to cool to room temperature and was purifiedwithout workup by prep HPLC on a C-18 column eluting water: acetonitrilegradient buffered pH 10 to give the title compound as a white amorphoussolid (0.035 g, 50%). The product was isolated as a single enantiomer.LCMS calculated for C₂₅H₃₄N₇O₂ (M+H)⁺: m/z=464.3; found: 464.3. ¹H NMR(300 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.23 (s, 1H), 6.21 (q, J=6.8 Hz, 1H),4.00 (m, 4H), 3.81-3.54 (m, 2H), 3.15 (m, 2H), 2.53 (s, 3H), 2.33 (s,3H), 2.27 (bs, 2H), 1.70 (d, J=7.1 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 1.04(s, 6H).

Example 322.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]-6-methylbenzonitrile

The4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-ethoxy-6-methylbenzonitrile(0.075 g, 0.10 mmol, chiral intermediate from Example 320, Step 1) wasdissolved in N,N-dimethylformamide (3.0 mL) and DIPEA (0.089 mL, 0.51mmol) and the propanoic acid, 2-hydroxy-2-methyl- (0.013 g, 0.12 mmol)and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.058 g, 0.15 mmol) were added. The reaction wasstirred at room temperature for 18 hrs and was complete by LC/MS. Theproduct was purified without workup by prep HPLC on a C-18 columneluting water: acetonitrile gradient buffered to pH 10 to give the titlecompound as a white amorphous solid (0.025 g, 51%). The product wasisolated as a single enantiomer. LCMS calculated for C₂₅H₃₂N₇O₃ (M+H)⁺:m/z=478.2; found: 478.2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.29(s, 1H), 6.24 (q, J=6.8 Hz, 1H), 5.07 (s, 1H), 4.90-4.75 (m, 1H),4.73-4.58 (m, 1H), 4.39 (p, J=8.5 Hz, 1H), 4.30-4.05 (m, 2H), 3.75 (d,J=7.1 Hz, 2H), 2.54 (s, 3H), 2.38 (s, 3H), 1.72 (d, J=6.9 Hz, 3H), 1.35(t, J=6.1 Hz, 3H), 1.26 (s, 3H), 1.23 (s, 3H).

Compounds Synthesized

Experimental procedures for compound Examples 326-344 are summarized inTables 7 and 8.

TABLE 7

Ex. No. Name R² R⁴ R⁵ R⁶ Salt Proc.¹ 326 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-3-ethoxy-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-6- Et CN CH₃

321 methylbenzonitrile³ 327 4-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-3-ethoxy-2-[1-(2-hydroxyethyl)azetidin-3-yl]-6- Et CN CH₃

320 methylbenzonitrile³ 328 4-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-2-[l-(2-hydroxy-2-methylpropyl)azetidin-3-yl]-3- CH₃ CN CH₃

315 methoxy-6-methylbenzonitrile ¹Synthesized according to theexperimental procedure of compound listed; ²Compound isolated as aracemic mixture; ³Compound isolated as a single enantiomer.

TABLE 8

Ex. No. Name R² R⁴ R⁵ R³ Salt Proc.¹ 329 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)ethyl]-6-chloro-3-ethoxy-2-pyrimidin-5-ylbenzonitrile² Et CN Cl

TFA  43 330 5-{3-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}nicotinonitrile³ Et CN Cl

TFA  43 331 5-{3-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}-N,N- dimethylnicotinamide³Et CN Cl

 43 332 4-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[5- (methylsulfonyl)pyridin-3-yl]benzonitrile³ Me CN Cl

313 333 5-{3-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}-N-methylpyridine-2-carboxamide² Et CN Cl

 43 334 4-{3-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide³ Et CN Cl

 43 335 4-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-6-methyl-2-[5- (methylsulfonyl)pyridin-3-yl]benzonitrile³ Et CN CH₃

314 336 4-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[6- (2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]benzonitrile² Et CN Cl

 43 337 4-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[6- (2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl]benzonitrile² Et CN Cl

 43 338 4-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[6- (5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]benzonitrile² Et CN Cl

 43 339 4-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[5- (1,3-oxazol-2-yl)pyridin-3-yl]benzonitrile² Et CN Cl

 43 340 4-{3-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5- methylphenyl}-N,N-dimethylpyridine-2-carboxamide³ Et CN CH₃

314 341 4-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[3- (methoxymethyl)azetidin-1-yl]benzonitrile² Et CN Cl

321 342 1-{3-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2- ethoxyphenyl}azetidine-3- carbonitrile² EtCN Cl

319 343 4-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-6-methyl-2-(1- methyl-1H-pyrazol-4- yl)benzonitrile²Et CN CH₃

314 344 5-{3-[1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5- methylphenyl}-N,N-dimethylpyridine-2-carboxamide³ Me CN CH₃

317 ¹Synthesized according to the experimental procedure of compoundlisted; ²Compound isolated as a racemic mixture; ³Compound isolated as asingle enantiomer.Analytical Data

¹H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer,or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data(MS) for the compounds of Examples 326-344 is provided in Table 9

TABLE 9 Ex. MS No. [M + H]⁺ Solvent MHz ¹H NMR Spectra 329 435.1 DMSO-500 ¹H NMR (500 MHz, DMSO) δ 9.33 (s, 1H), 9.04 (s, d₆ 2H), 8.18 (s,1H), 7.81 (s, 1H), 6.36 (q, J = 7.0 Hz, 1H), 3.56 (td, J = 14.1, 7.0 Hz,1H), 3.39 (dq, J = 14.1, 6.9 Hz, 1H), 2.59 (s, 3H), 1.81 (d, J = 7.0 Hz,3H), 0.94 (t, J = 7.0 Hz, 3H). 330 459.1 DMSO- 500 ¹H NMR (500 MHz,DMSO) δ 9.18 (d, J = 1.9 Hz, d₆ 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.63 (t,J = 2.0 Hz, 1H), 8.33 (s, 1H), 7.82 (s, 1H), 6.38 (q, J = 7.0 Hz, 1H),3.56-3.44 (m, 1H), 3.43-3.33 (m, 1H), 2.61 (s, 3H), 1.83 (d, J = 7.0 Hz,3H), 0.92 (t, J = 7.0 Hz, 3H). 331 505.2 DMSO- 300 ¹H NMR (300 MHz,dmso) δ 8.77 (d, J = 2.2 Hz, 1H), d₆ 8.73 (d, J = 1.9 Hz, 1H), 8.10 (d,J = 3.9 Hz, 2H), 7.74 (s, 1H), 6.33 (d, J = 7.4 Hz, 1H), 3.52 (m, 1H),3.39 (m, 1H), 3.00 (s, 3H), 2.94 (s, 3H), 2.56 (s, 3H), 1.79 (d, J = 7.0Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H). 332 498.1 DMSO- 500 ¹H NMR (500 MHz,DMSO) δ 9.21 (d, J = 2.2 Hz, d₆ 1H), 9.11 (d, J = 1.9 Hz, 1H), 8.58 (t,J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 6.34 (q, J = 7.0 Hz, 1H),3.37 (s, 3H), 3.30 (s, 3H), 2.58 (s, 3H), 1.81 (d, J = 7.1 Hz, 3H). 333491.1 CD₃OD 300 ¹H NMR (300 MHz, CD₃OD) δ 8.80 (d, J = 1.9 Hz, 1H), 8.27(d, J = 8.1 Hz, 1H), 8.19 (d, J = 10.3 Hz, 2H), 7.80 (s, 1H), 6.47 (q, J= 7.2 Hz, 1H), 3.64-3.38 (m, 2H), 3.04 (s, 3H), 2.68 (s, 3H), 1.93 (d, J= 7.1 Hz, 3H), 1.01 (t, J = 7.0 Hz, 3H). 334 505.2 CD₃OD 300 ¹H NMR (300MHz, CD₃OD) δ 8.80 (d, J = 5.0 Hz, 1H), 8.17 (s, 1H), 7.80 (d, J = 3.4Hz, 2H), 7.71 (d, J = 4.9 Hz, 1H), 6.47 (m, J = 7.1 Hz, 1H), 3.69-3.42(m, 2H), 3.19 (s, 3H), 3.08 (s, 3H), 2.67 (s, 3H), 1.92 (d, J = 7.1 Hz,3H), 1.07 (t, J = 6.9 Hz, 3H). 335 492.2 DMSO- 300 ¹H NMR (300 MHz,dmso) δ 9.16 (d, J = 2.2 Hz, 1H), d₆ 9.07 (d, J = 2.0 Hz, 1H), 8.54 (t,J = 2.1 Hz, 1H), 8.10 (s, 1H), 7.56 (s, 1H), 6.34 (q, J = 7.1 Hz, 1H),3.57-3.42 (m, 1H), 3.38 (s, 3H), 3.30-3.19 (m, 1H), 2.56 (s, 3H), 2.47(s, 3H), 1.79 (d, J = 7.1 Hz, 3H), 0.90 (t, J = 6.9 Hz, 3H). 336 516.1DMSO- 300 ¹H NMR (300 MHz, dmso) δ 8.99 (d, J = 1.5 Hz, 1H), d₆ 8.42 (d,J = 8.2 Hz, 1H), 8.31 (dd, J = 8.2, 2.2 Hz, 1H), 8.11 (s, 1H), 7.77 (s,1H), 6.35 (q, J = 6.8 Hz, 1H), 4.45 (s, 3H), 3.64-3.47 (m, 1H),3.44-3.33 (m, 1H), 2.57 (s, 3H), 1.80 (d, J = 7.1 Hz, 3H), 0.94 (t, J =6.9 Hz, 3H). 337 515.2 DMSO- 400 ¹H NMR (400 MHz, dmso) δ 8.78 (dd, J =2.2, 0.9 Hz, d₆ 1H), 8.32 (s, 1H), 8.12-8.08 (m, 2H), 8.04 (dd, J = 8.2,0.8 Hz, 1H), 7.73 (s, 1H), 6.35 (q, J = 7.1 Hz, 1H), 4.25 (s, 3H), 3.44(ddd, J = 57.4, 9.1, 7.0 Hz, 2H), 2.57 (s, 3H), 1.80 (d, J = 7.1 Hz,3H), 0.93 (t, J = 7.0 Hz, 3H). 338 516.2 CD₃OD 300 ¹H NMR (300 MHz,CD₃OD) δ 8.93 (d, J = 1.3 Hz, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.29 (dd, J= 8.2, 2.2 Hz, 1H), 8.17 (s, 1H), 7.83 (s, 1H), 6.49 (q, J = 7.0 Hz,1H), 3.72-3.55 (m, 1H), 3.55-3.40 (m, 1H), 2.73 (s, 3H), 2.68 (s, 3H),1.94 (d, J = 7.1 Hz, 3H), 1.04 (t, J = 7.0 Hz, 3H). 339 501.2 DMSO- 400¹H NMR (400 MHz, dmso) δ 9.27 (d, J = 2.1 Hz, 1H), d₆ 8.88 (d, J = 2.1Hz, 1H), 8.56 (t, J = 2.1 Hz, 1H), 8.36 (d, J = 0.7 Hz, 1H), 8.12 (s,1H), 7.77 (s, 1H), 7.49 (d, J = 0.7 Hz, 1H), 6.36 (q, J = 7.0 Hz, 1H),3.55 (dd, J = 9.1, 7.0 Hz, 1H), 3.47-3.33 (m, 1H), 2.58 (s, 3H), 1.80(d, J = 7.1 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H). 340 485.2 CD₃OD 300 ¹HNMR (300 MHz, CD₃OD) δ 8.77 (dd, J = 5.1, 0.8 Hz, 1H), 8.16 (s, 1H),7.76 (dd, J = 1.6, 0.8 Hz, 1H), 7.69 (dd, J = 5.1, 1.7 Hz, 1H), 7.59 (s,1H), 6.46 (q, J = 7.1 Hz, 1H), 3.63-3.39 (m, 2H), 3.19 (s, 3H), 3.08 (s,3H), 2.66 (s, 3H), 2.56 (s, 3H), 1.92 (d, J = 7.1 Hz, 3H), 1.04 (t, J =7.0 Hz, 3H). 341 456.2 DMSO- 500 ¹H NMR (500 MHz, DMSO) δ 8.11 (s, 1H),6.79 (s, d₆ 1H), 6.18 (q, J = 6.9 Hz, 1H), 4.37 (q, J = 8.4 Hz, 2H),4.08-3.97 (m, 2H), 3.82-3.62 (m, 2H), 3.51 (d, J = 6.5 Hz, 2H), 3.27 (s,3H), 2.90-2.77 (m, 1H), 2.55 (s, 3H), 1.69 (d, J = 7.0 Hz, 3H), 1.34 (t,J = 7.0 Hz, 3H). 342 437.1 CD₃OD 300 ¹H NMR (300 MHz, CD₃OD) δ 8.13 (s,1H), 6.95 (s, 1H), 6.30 (q, J = 7.2 Hz, 1H), 4.63 (t, J = 8.6 Hz, 2H),4.46 (ddd, J = 8.3, 6.0, 1.9 Hz, 2H), 3.94-3.56 (m, 3H), 2.61 (s, 3H),1.78 (d, J = 7.1 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H). 326 450.3 DMSO- 300¹H NMR (300 MHz, dmso) δ 8.09 (s, 1H), 7.24 (s, d₆ 1H), 6.21 (q, J = 6.8Hz, 1H), 4.41 (bs, 1H), 4.02 (m, J = 20.9 Hz, 3H), 3.81-3.47 (m, 3H),3.14 (m, 2H), 2.54 (s, 3H), 2.34 (s, 5H), 1.70 (d, J = 7.1 Hz, 3H), 1.31(t, J = 6.9 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). 343 417.3 CD₃OD 300 ¹HNMR (300 MHz, CD₃OD) δ 8.12 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.34(s, 1H), 6.39 (q, J = 7.1 Hz, 1H), 3.97 (s, 3H), 3.60-3.41 (m, 2H), 2.61(s, 3H), 2.46 (s, 3H), 1.84 (d, J = 7.0 Hz, 3H), 1.14 (t, J = 7.0 Hz,3H). 327 436.2 DMSO- 300 ¹H NMR (300 MHz, dmso) δ 8.09 (s, 1H), 7.23 (s,d₆ 1H), 6.21 (d, J = 7.0 Hz, 1H), 4.39 (t, J = 5.4 Hz, 1H), 4.10-3.81(m, 3H), 3.69 (dt, J = 15.5, 7.8 Hz, 2H), 3.36 (m, 2H), 3.12-2.97 (m,2H), 2.54 (s, 3H), 2.45-2.38 (m, 2H), 2.34 (s, 3H), 1.70 (d, J = 7.1 Hz,3H), 1.31 (t, J = 6.9 Hz, 3H). 344 471.2 DMSO- 300 ¹H NMR (300 MHz,dmso) δ 8.67 (d, J = 1.5 Hz, 1H), d₆ 8.10 (s, 1H), 8.06 (dd, J = 8.0,2.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 6.32 (q, J = 7.0Hz, 1H), 3.26 (s, 3H), 3.03 (s, 3H), 2.96 (s, 3H), 2.57 (s, 3H), 2.45(s, 3H), 1.79 (d, J = 7.0 Hz, 3H). 328 450.2 DMSO- 300 ¹H NMR (300 MHz,dmso) δ 8.08 (s, 1H), 7.20 (s, d₆ 1H), 6.21 (q, J = 6.9 Hz, 1H), 4.04(s, 1H), 4.03-3.91 (m, 3H), 3.58 (s, 3H), 3.15-3.02 (m, 2H), 2.54 (s,3H), 2.32 (s, 3H), 2.25 (s, 2H), 1.70 (d, J = 7.1 Hz, 3H), 1.03 (s, 6H).

Examples 310 and 311. Diastereoisomers of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}pyrrolidin-2-one

Step 1. 1-(5-Chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanol

The desired compound was prepared according to the procedure of Example212, step 4 (racemic mixture), using1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone instead oftert-butyl3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate asthe starting material in 94% yield as a 96:4 mixture of enantiomers(RT=3.56 min and 4.28 min; Chiral Technologies ChiralPak AD-H column,20×250 mm, 5 micron particle size, eluting with 5% ethanol in hexanes at1 ml/min). LCMS for C₁₁H₁₃ClIO (M-(OH))⁺: m/z=323.0; Found: 322.9.

Step 2.1-[1-(5-Chloro-2-ethoxy-3-iodo-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

The desired compound was prepared according to the procedure of Example212, step 5, using 1-(5-Chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanol(96:4 mixture from step 1) instead of tert-butyl3-[3-chloro-2-cyano-6-ethoxy-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylateas the starting material in 32% yield as a single enantiomer (peak 1desired, retention time=3.39 min; ChiralPak IA column, 20×250 mm, 5micron particle size, eluting with 3% ethanol in hexanes at 18 ml/min).LCMS for C₁₇H₂₀ClIN₅O (M+H)⁺: m/z=472.0; Found: 472.0.

Step 3. Methyl(2E)-3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}acrylate

A suspension of1-[1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (peak 1 single isomer from step 2) (0.61 g, 1.3mmol) in acetonitrile (7.4 mL) in a sealed tube was degassed withnitrogen and treated with triphenylphosphine (0.048 g, 0.18 mmol),methyl acrylate (0.41 mL, 4.5 mmol), and palladium acetate (0.029 g,0.13 mmol) followed by triethylamine (0.54 mL, 3.9 mmol) and heated at100° C. for 16 h. The reaction mixture was cooled to room temperature,filtered, and the solids washed with acetonitrile. The filtrate wasconcentrated to a residue. The crude material was purified by flashcolumn chromatography using ethyl acetate (containing 3% methanol) inhexanes (0%-100%) to give the desired product (0.40 g, 72%). LCMS forC₂₁H₂₅ClN₅O₃ (M+H)⁺: m/z=430.2; Found: 430.2.

Step 4. Diastereoisomers of methyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-4-nitrobutanoate

A solution of methyl(2E)-3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}acrylate(0.40 g, 0.93 mmol) in nitromethane (6.3 mL) was treated with1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.93 mmol) and stirred at90° C. for 22 h. The reaction mixture was concentrated, diluted withmethanol, and purified by preparative LCMS (XBridge C18 Column, elutingwith a gradient of acetonitrile in water with 0.1% trifluoroacetic acid,at flow rate of 60 mL/min). The LCMS fractions were concentrated toremove acetonitrile, treated with solid sodium bicarbonate, andextracted into ethyl acetate. The ethyl acetate was concentrated to givethe desired product (0.22 g, 48%) as a mixture of diastereoisomers. LCMSfor C₂₂H₂₈ClN₆O₅(M+H)⁺: m/z=491.2; Found: 491.2.

Step 5. Diastereoisomers of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}pyrrolidin-2-on

A solution of methyl3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-4-nitrobutanoate(0.089 g, 0.18 mmol) in methanol (1.3 mL) was treated with nickelchloride hexahydrate (0.087 g, 0.36 mmol) was and stirred for 5 min. Thereaction mixture was cooled to 0° C., treated with sodiumtetrahydroborate (0.073 g, 1.9 mmol) in four portions, and stirred atroom temperature for 30 min. The reaction mixture was heated at 60° C.for 1.5 h, cooled to room temperature, diluted with saturated sodiumbicarbonate solution (10 mL) and dichloromethane (25 mL), and filteredthrough Celite. The Celite was washed with dichloromethane and thefiltrate was transferred to a separatory funnel. The organic layer wasseparated, washed with brine, dried over sodium sulfate, filtered, andconcentrated to residue. The crude residue was diluted with methanol andpurified by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired peak 1 diastereoisomer (16mg, 21%) and peak 2 diastereoisomer (19 mg, 24%). Peak 1 (compound 310):¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.89 (s, 1H), 7.34 (s, 1H),6.21 (q, J=7.1 Hz, 1H), 4.38-4.22 (m, 1H), 3.93-3.80 (m, 1H), 3.79-3.67(m, 1H), 3.65-3.55 (m, 1H), 3.28-3.20 (m, 1H), 2.54 (s, 3H), 2.29 (dd,J=17.5, 8.3 Hz, 1H), 2.21 (s, 3H), 1.70 (d, J=7.0 Hz, 3H), 1.40 (t,J=6.9 Hz, 3H). LCMS for C₂₁H₂₆ClN₆O₂ (M+H)⁺: m/z=429.2; Found: 429.2.Peak 2 (compound 311): ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.89(s, 1H), 7.33 (s, 1H), 6.20 (q, J=7.1 Hz, 1H), 4.38-4.22 (m, 1H),3.90-3.68 (m, 2H), 3.65-3.56 (m, 1H), 3.28-3.17 (m, 1H), 2.54 (s, 3H),2.32 (dd, J=17.3, 8.5 Hz, 1H), 2.21 (s, 3H), 1.69 (d, J=7.0 Hz, 3H),1.39 (t, J=6.9 Hz, 3H). LCMS for C₂₁H₂₆ClN₆O₂ (M+H)⁺: m/z=429.2; Found:429.2.

Example 323.4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile

Step 1. 4-Acetyl-6-chloro-3-ethoxy-2-vinylbenzonitrile

A mixture of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (1.3 g, 3.6mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (740 μL, 4.3mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (100 mg, 0.20 mmol) and potassiumcarbonate (1.5 g, 11 mmol) in 1,4-dioxane (20 mL) and water (10 mL) washeated at 80° C. overnight. The mixture was cooled to room temperatureand extracted with ethyl acetate. The extracts were washed with brine,dried over sodium sulfate, filtered and concentrated. Purification onsilica gel using ethyl acetate in hexanes (0-20%) gave the desiredcompound, 780 mg, 87%. LCMS calculated for C₁₃H₁₃ClNO₂ (M+H)⁺:m/z=250.1; found: 250.1. ¹H NMR (400 MHz, DMSO-d₆): δ 7.78 (s, 1H), 6.83(m, 1H), 6.10 (m, 1H), 5.83 (m, 1H), 3.84 (m, 2H), 2.58 (s, 3H), 1.22(m, 3H).

Step 2. tert-Butyl[2-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)-2-hydroxyethyl]carbamate

0.2 M Osmium tetraoxide in water (0.5 mL) was added to a solution oftert-butyl [(4-chlorobenzoyl)oxy]carbamate (Ref. Lawrence Harris, J.Org. Chem, 2011, 76, 358-372). (0.91 g, 3.3 mmol) in acetonitrile (10mL) and stirred for 10 minutes.4-Acetyl-6-chloro-3-ethoxy-2-vinylbenzonitrile (0.56 g, 2.2 mmol) as asolution in acetonitrile (10 mL) was added to the carbamate solutionfollowed by the addition of water (2 mL) and the reaction was stirredfor 3 hours at room temperature. The reaction was quenched withsaturated 10 M dipotassium disulfite in water (12 mL) and stirred for 5minutes. Water was added and the reaction mixture was extracted withethyl acetate. The extracts were washed with saturated sodiumbicarbonate solution, brine and dried over sodium sulfate, filtered andevaporated. Purification on silica gel using ethyl acetate in hexane(0-100%) gave the desired compound as a racemic mixture, 610 mg, 72%.LCMS calculated for C₁₈H₂₄ClN₂O₅(M+H)⁺: m/z=383.1; found: 383.1. ¹H NMR(400 MHz, DMSO-d₆): δ 7.62 (s, 1H), 7.03 (br s, 1H), 5.68 (br s, 1H),3.96 (m, 1H), 3.69 (m, 1H), 3.31 (m, 1H), 3.19 (m, 1H), 2.60 (s, 3H),1.30 (m, 12H).

Step 3.4-Acetyl-6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile

tert-Butyl[2-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)-2-hydroxyethyl]carbamate(290 mg, 0.76 mmol) (racemic mixture from step 2) was treated with 4.0 Mhydrogen chloride in 1,4-dioxane (6.1 mL) for 15 minutes and the mixturewas evaporated. The residue was dissolved in tetrahydrofuran (2.3 mL)and N,N-diisopropylethylamine (0.66 mL, 3.8 mmol).N,N-carbonyldiimidazole (250 mg, 1.5 mmol) was added and the reactionmixture was refluxed at 70° C. overnight. The reaction mixture wasevaporated. Purification on silica gel using ethyl acetate in hexane(0-100%) gave the desired compound as a racemic mixture, 110 mg, 47%.LCMS calculated for C₁₄H₁₄ClN₂O₄ (M+H)⁺: m/z=309.1; found: 309.1. ¹H NMR(400 MHz, DMSO-d₆): δ 8.00 (br s, 1H), 7.93 (s, 1H), 5.99 (m, 1H), 3.89(m, 1H), 3.81 (m, 2H), 3.52 (m, 1H), 2.58 (s, 3H), 1.23 (m, 3H).

Step 4.6-Chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile

Sodium tetrahydroborate (19 mg, 0.50 mmol) was added to a mixture of4-acetyl-6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile(100 mg, 0.34 mmol) (racemic mixture from step 3) in methanol (1.6 mL,38 mmol) at 0° C. and the reaction mixture was stirred at roomtemperature for 10 minutes and evaporated. The residue was diluted withethyl acetate, washed with 1 N HCl, brine, dried over sodium sulfate,filtered and concentrated to give the desired compound as a mixture offour diastereomers, 58 mg, 55%. LCMS calculated for C₁₄H₁₆ClN₂O₄ (M+H)⁺:m/z=311.1; found: 311.1.

Step 5.6-Chloro-4-(1-chloroethyl)-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile

To a mixture of6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile(58 mg, 0.19 mmol) (mixture of four diastereomers from step 4),N,N-dimethylformamide (36 μL) in methylene chloride (1 mL), thionylchloride (40 μL, 0.56 mmol) was added and the mixture was stirred atroom temperature for 20 minutes The mixture was diluted with methylenechloride, washed with saturated sodium bicarbonate, water, brine, driedover sodium sulfate, filtered and concentrated to give the desiredcompound as a mixture of four diastereomers, 55 mg, 91%. LCMS calculatedfor C₁₄H₁₅Cl₂N₂O₃ (M+H)⁺: m/z=329.0; found: 329.1.

Step 6.4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile

Cesium Carbonate (0.11 g, 0.34 mmol) was added to a mixture of3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.20 mmol) (mixtureof four diastereomers from step 5) in N,N-dimethylformamide (0.91 mL)and stirred for 10 minutes. To the mixture was added6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile(56 mg, 0.17 mmol) in N,N-dimethylformamide (1.0 mL) and the reactionwas stirred at 90° C. for 1 hour. Purification by preparative LCMS (pH10) using RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) gave the desired compounds as Peak 1 (racemic mixture of twodiastereomers) LCMS calculated for C₂₀H₂₁ClN₇O₃ (M+H)⁺: m/z=442.1;found: 442.1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (s, 1H), 8.00 (br s,1H), 7.79 (s, 1H), 6.25 (m, 1H), 5.92 (m, 1H), 3.90 (m, 3H), 3.57 (m,1H), 2.58 (s, 3H), 1.75 (m, 3H), 1.40 (m, 3H); Peak 2 (racemic mixtureof 2 diastereomers):

LCMS calculated for C₂₀H₂₁ClN₇O₃ (M+H)⁺: m/z=442.1; found: 442.1. ¹H NMR(400 MHz, DMSO-d₆): δ 8.12 (s, 1H), 8.00 (br s, 1H), 7.71 (s, 1H), 6.23(m, 1H), 5.96 (m, 1H), 3.85 (m, 3H), 3.58 (m, 1H), 2.58 (s, 3H), 1.75(m, 3H), 1.40 (m, 3H).

Chiral purification of Peak 2 (racemic mixture of two diastereomers) onPhenomenex Lux Cellulose-1, 21.2×250 mm, 5 micron particle size at 18mL/min using 20% ethanol in hexanes gave Peak 3 and Peak 4. Peak 3,retention time=12.22 minutes (single enantiomer): LCMS calculated forC₂₀H₂₁ClN₇O₃ (M+H)⁺: m/z=442.1; found: 442.1. ¹H NMR (400 MHz, DMSO-d₆):δ 8.12 (s, 1H), 7.98 (br s, 1H), 7.71 (s, 1H), 6.23 (m, 1H), 5.96 (m,1H), 3.85 (m, 3H), 3.58 (m, 1H), 2.58 (s, 3H), 1.75 (m, 3H), 1.40 (m,3H). Peak 4, retention time=16.25 minutes (single enantiomer). LCMScalculated for C₂₀H₂₁ClN₇O₃ (M+H)⁺: m/z=442.1; found: 442.1. ¹H NMR (400MHz, DMSO-d₆): δ 8.12 (s, 1H), 7.98 (br s, 1H), 7.71 (s, 1H), 6.23 (m,1H), 5.96 (m, 1H), 3.85 (m, 3H), 3.58 (m, 1H), 2.58 (s, 3H), 1.75 (m,3H), 1.40 (m, 3H).

Example 324.6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}morpholin-3-one

Step 1. 1-(5-Chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanone

A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (2.6g, 9.5 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.9 mL,11 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (400 mg, 0.5 mmol) and potassiumcarbonate (4.0 g, 29 mmol) in 1,4-dioxane (60 mL), and water (30 mL).The resulting mixture was heated at 80° C. for 3 hours. The mixture wascooled to room temperature and extracted with ethyl acetate.Purification on a silica gel using ethyl acetate in hexanes (0-20%) gavethe desired compound, 2.0 g, 94%. LCMS calculated for C₁₂H₁₄ClO₂ (M+H)⁺:m/z=225.1; found: 225.1.

Step 2. tert-Butyl[2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]carbamate

0.2 M Osmium tetraoxide in water (1 mL) was added to a solution oftert-butyl [(4-chlorobenzoyl)oxy]carbamate (2.0 g, 7.2 mmol) (Ref.Lawrence Harris, J. Org. Chem, 2011, 76, 358-372) in acetonitrile (22mL) and stirred for 10 minutes.1-(5-Chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanone (1.1 g, 4.8 mmol)as a solution in acetonitrile (22 mL) was added to the carbamatesolution followed by the addition of water (5 mL). The reaction wasstirred for 3 hours at room temperature. The reaction was quenched withsaturated 10 M dipotassium disulfite in water (25 mL) and stirred for 5minutes. Water was added to the reaction and the mixture was extractedwith ethyl acetate. The organic extracts were washed with saturatedsodium bicarbonate solution, brine, dried over sodium sulfate andevaporated under reduced pressure. Purification on silica gel usingethyl acetate in hexane (0-100%) gave the desired compound as a racemicmixture, 1.2 g, 69%. LCMS calculated for C₁₇H₂₄ClNO₅Na (M+Na)⁺:m/z=380.1; found: 380.1. ¹H NMR (500 MHz, DMSO-d₆): δ 7.48 (s, 1H), 6.80(m, 1H), 5.50 (br s, 1H), 5.20 (br s, 1H), 3.83 (s, 3H), 3.32 (m, 1H),3.22 (m, 1H), 2.59 (s, 3H), 2.55 (s, 3H), 1.32 (s, 9H).

Chiral purification on ChiralPak AD-H, 20×250 mm (Chiral Technologies),5 micron particle size, at flow rate of 18 mL/min using 8% ethanol inhexanes gave the Peak 1 (single enantiomer) (retention time=9.86minutes) and Peak 2 (single enantiomer) (retention time=11.47 minutes).

Step 3.N-[2-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]-2-chloroacetamide

tert-Butyl[2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]carbamate(170 mg, 0.47 mmol) (Peak 1 from step 2) was treated with 4.0 M hydrogenchloride in 1,4-dioxane (12 mL) for 15 minutes. The solvents wereevaporated, methylene chloride (6 mL) and triethylamine (200 μL, 1.4mmol) were added and the mixture cooled to 0° C. Chloroacetyl chloride(45 μL, 0.56 mmol) was added slowly and was stirred for 10 minutes at 0°C. The solvents were evaporated to dryness. Water was added and themixture was extracted with ethyl acetate. The combined extracts werewashed with brine, dried over sodium sulfate, and concentrated to givethe crude residue as a single enantiomer. LCMS calculated forC₁₄H₁₇Cl₂NO₄Na (M+Na)⁺: m/z=356.1; found: 356.1.

Step 4. 6-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl) morpholin-3-one

To a solution ofN-[2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]-2-chloroacetamide(170 mg, 0.50 mmol) (single enantiomer from step 3) in tetrahydrofuran(4 mL) cooled at 0° C., a mixture of sodium hydride (60% dispersion inmineral oil; 39 mg, 1.0 mmol) was added and stirred for 1 hour. Thereaction was quenched with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over sodium sulfate, andconcentrated to give the crude residue as a single enantiomer, 61 mg,41%. LCMS calculated for C₁₄H₁₇ClNO₄ (M+H)⁺: m/z=298.1; found: 298.1.

Step 5.6-[3-Chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]morpholin-3-one

To a solution of6-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)morpholin-3-one (27 mg,0.090 mmol) (single enantiomer from step 4) in methanol (2 mL) was addedsodium tetrahydroborate (6.8 mg, 0.18 mmol) at 0° C. and stirred for 1hour. Purification by preparative LCMS (pH 10) gave the desired compoundas a racemic mixture of two diastereomers, 20 mg, 76%. LCMS calculatedfor C₁₄H₁₇ClNO₃ (M-OH)⁺: m/z=282.1; found: 282.1.

Step 6.6-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]morpholin-3-one

A mixture of thionyl chloride (15 μL, 0.21 mmol) andN,N-dimethylformamide (10.0 μL) was stirred at room temperature for 10minutes. A solution of6-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]morpholin-3-one(19.0 mg, 0.0634 mmol) (racemic mixture of two diastereomers from step5) in methylene chloride (1.0 mL) was added and the mixture was stirredat room temperature overnight. The mixture was diluted with methylenechloride, washed with saturated sodium bicarbonate, water, brine, driedover sodium sulfate, filtered and concentrated to give the desiredcompound as a racemic mixture of two diastereomers, 19 mg, 94%. LCMScalculated for C₁₄H₁₇ClNO₃ (M-Cl)⁺: m/z=282.1; found: 282.1.

Step 7.6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}morpholin-3-one

A mix of6-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]morpholin-3-one(19.0 mg, 0.0597 mmol) (racemic mixture of two diastereomers from step6) 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (11 mg, 0.072 mmol),cesium carbonate (29 mg, 0.090 mmol) and potassium iodide (0.99 mg,0.006 mmol) in N,N-dimethylformamide (0.19 mL) was heated at 140° C. for1 hour. The mixture was diluted with ether, washed with water,concentrated and purified by preparative LCMS (pH 10) using RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give2.5 mg, 10% of Peak 1 (single enantiomer, retention time 10.15 min):LCMS calculated for C₂₀H₂₄ClN₆O₃ (M+H)⁺: m/z=431.2; found: 431.1, and2.7 mg, 10% of Peak 2 (single enantiomer, retention time 10.76 min):LCMS calculated for C₂₀H₂₄ClN₆O₃ (M+H)⁺: m/z=431.2; found: 431.1.

Example 325.5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-1,3-oxazolidin-2-one

Step 1.5-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)-1,3-oxazolidin-2-one

To a solution of tert-butyl[2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]carbamate(140 mg, 0.40 mmol) (Peak 1, single enantiomer from step 2, Example 324)in tetrahydrofuran (2.5 mL), N,N-diisopropylethylamine (0.35 mL, 2.0mmol) and N,N-carbonyldiimidazole (130 mg, 0.80 mmol). The reaction wasrefluxed at 70° C. for 10 minutes. The reaction was evaporated todryness. Purification on silica gel using (0-50%) ethyl acetate inhexane gave the desired compound as a single enantiomer, 78 mg, 69%.LCMS calculated for C₁₃H₁₅ClNO₄ (M+H)⁺: m/z=284.1; found: 284.1.

Step 2.5-[3-Chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-1,3-oxazolidin-2-one

To a solution of5-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-1,3-oxazolidin-2-one (21mg, 0.072 mmol) (single enantiomer from step 1) in methanol (1 mL) wasadded sodium tetrahydroborate (5.5 mg, 0.14 mmol) at 0° C. The mixturewas stirred at 0° C. for 1 hour. It was diluted with methanol andpurified on preparative LCMS using pH 10 buffer to give the desiredcompound as a racemic mixture of two diastereomers, 17 mg, 83%. LCMScalculated for C₁₃H₁₅ClNO₃ (M-OH)⁺: m/z=268.1; found: 268.1.

Step 3.5-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-1,3-oxazolidin-2-one

A mixture of cyanuric chloride (16 mg, 0.084 mmol) andN,N-dimethylformamide (15 μL) was stirred at room temperature for 10minutes. A solution of5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-1,3-oxazolidin-2-one(16 mg, 0.056 mmol) (racemic mixture of two diastereomers from step 2)in methylene chloride (0.3 mL) was added and the reaction was stirred atroom temperature overnight. Thionyl chloride (12 μL, 0.17 mmol) wasadded and stirred for 10 min. The mixture was diluted with methylenechloride, washed with saturated sodium bicarbonate, water, brine, driedover sodium sulfate, filtered and concentrated to give the desiredcompound as a racemic mixture of two diastereomers, 17 mg, 100%. LCMScalculated for C₁₃H₁₆Cl₂NO₃ (M+H)⁺: m/z=304.0; found: 304.1.

Step 4.5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-1,3-oxazolidin-2-one

A mixture of5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-1,3-oxazolidin-2-one(17 mg, 0.056 mmol) (racemic mixture of two diastereomers from step 3)3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.067 mmol), cesiumcarbonate (27 mg, 0.084 mmol) and potassium iodide (0.93 mg, 0.0056mmol) in N,N-dimethylformamide (0.18 mL) was heated at 140° C. for 1hour. The mixture was diluted with ether, washed with water,concentrated and purified by preparative LCMS (pH 10) to give thedesired compound as a racemic mixture of two diastereomers, 2.2 mg, 9%;LCMS calculated for C₁₉H₂₂ClN₆O₃ (M+H)⁺: m/z=417.1; found: 417.1.

Examples 345-348. Diastereoisomers of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one

Step 1. 1-(5-Chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanol

A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (20.0g, 58.4 mmol; Example 212, step 1) and 1,2-ethanediol (6.5 mL, 120 mmol)in toluene (190 mL) was treated with p-toluenesulfonic acid monohydrate(1.1 g, 5.8 mmol). The flask was fitted with a Dean-Stark trap that wasfilled with sieves, and refluxed for 3 h. The reaction mixture wascooled and added to ice cooled saturated sodium bicarbonate solution(250 mL) and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, filtered, and concentrated to acrude orange oil. The crude material was purified by flash columnchromatography using ethyl acetate in hexanes (0%-20%) to give thedesired product (22 g, 99%). LCMS for C₁₂H₁₄ClFIO₃ (M+H)⁺: m/z=387.0;Found: 386.9.

Step 2. Ethyl(2E)-3-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]acrylate

A mixture of2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane (22g, 58 mmol) (from Step 1), ethyl(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (16 mL, 70mmol), and potassium carbonate (24 g, 170 mmol) in 1,4-dioxane (230 mL)and water (110 mL) was degassed with nitrogen for 10 min. The reactionmixture was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1:1) (2.4 g, 2.9 mmol), degassed with nitrogen foranother 10 min, and heated at 80° C. for 2 h. The reaction mixture wasfiltered through Celite and washed with ethyl acetate (300 mL). Thefiltrate was poured into water (400 mL). The aqueous layer was separatedand extracted with additional ethyl acetate (300 mL). The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered, and concentrated to a crude brown solid. The crude materialwas purified by flash column chromatography using ethyl acetate inhexanes (0%-30%) to give the desired product (20 g, 96%). ¹H NMR (400MHz, CDCl₃) δ 7.74 (d, J=16.5 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 6.70 (dd,J=16.5, 0.9 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.10-3.99 (m, 2H), 3.91 (q,J=7.0 Hz, 2H), 3.87-3.76 (m, 2H), 1.73 (s, 3H), 1.44 (t, J=7.0 Hz, 3H),1.33 (t, J=7.1 Hz, 3H). LCMS for C₁₇H₂₁ClFO₅ (M+H)⁺: m/z=359.1; Found:359.1.

Step 3. Ethyl3-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-4-nitrobutanoate

A solution ethyl(2E)-3-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]acrylate(10 g, 28 mmol) (from Step 2) in nitromethane (100 mL) was treated with1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 mL, 31 mmol) and stirred at 60°C. for 15 h. The reaction mixture was poured into water (400 mL) andextracted with ethyl acetate (2×300 mL). The combined organic extractswere washed with brine, dried over sodium sulfate, filtered, andconcentrated to a crude orange oil. The crude material was purified byflash column chromatography using ethyl acetate in hexanes (0%-30%) togive the desired product as a mixture of enantiomers (10.4 g, 89%). ¹HNMR (400 MHz, CDCl₃) δ 7.52 (d, J=9.1 Hz, 1H), 4.82 (ddd, J=12.5, 7.6,1.4 Hz, 1H), 4.68 (dd, J=12.5, 7.2 Hz, 1H), 4.54-4.40 (m, 1H), 4.15-3.90(m, 6H), 3.89-3.75 (m, 2H), 2.85 (ddd, J=16.0, 8.6, 1.4 Hz, 1H), 2.73(dd, J=16.1, 6.2 Hz, 1H), 1.70 (s, 3H), 1.47 (t, J=7.0 Hz, 3H), 1.21 (t,J=7.1 Hz, 3H). LCMS for C₁₈H₂₄ClFNO₇ (M+H)⁺: m/z=420.1; Found: 420.1.

Step 4. Enantiomers4-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]pyrrolidin-2-one

A suspension of ethyl3-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-4-nitrobutanoate(1.0 g, 2.4 mmol) (from Step 3) in ethanol (16 mL) was warmed todissolve the solid. The solution was cooled back to ambient temperature,degassed with nitrogen, and treated with a slurry of 2800 Raney Nickelin water (1.5 mL). The reaction mixture was degassed again with nitrogenand hydrogenated with a balloon of hydrogen for 3 h. The reactionmixture was filtered through Celite and concentrated to give theintermediate amino ester (0.93 g, 100%). The intermediate amino esterwas dissolved in toluene (12 mL) and heated at 110° C. for 12 h. Thereaction mixture was cooled to ambient temperature, at which point asolid precipitated from solution. This mixture was cooled to 0° C.,stirred for 30 min, filtered, washed with cold toluene, and dried togive the desired product as a mixture of enantiomers (0.61 g, 75%). LCMSfor C₁₆H₂₀ClFNO₄ (M+H)⁺: m/z=344.1; Found: 344.1. The mixture ofenantiomers was separated by chiral HPLC to give the individualenantiomers as peak 1 and peak 2 (RT=5.39 min and 7.01 min,respectively; Phenomenex Lux Cellulose C-1, 21.2×250 mm, 5 micronparticle size, eluting with 20% ethanol in hexanes at 18 mL/min).

Step 5. Enantiomers of4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

The separated enantiomers from step 4 were each processed individuallyto the final compounds. A solution of4-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]pyrrolidin-2-one(1.7 g, 5.0 mmol) (from Step 4) in methanol (17 mL) was treated with 6.0M hydrogen chloride in water (11 mL, 69 mmol) dropwise and stirred 20°C. for 30 min. The reaction mixture was added dropwise to ice cooledsaturated sodium bicarbonate solution (75 ml) and extracted with ethylacetate (2×100 ml). The combined organic extracts were washed withbrine, dried over sodium sulfate, filtered, and concentrated to give thedesired products [from peak 1 (1.5 g, 99%); from peak 2 (1.5 g, 99%)]that were used without further purification. From peak 1: ¹H NMR (400MHz, DMSO-d₆) δ 7.84 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 4.16-3.99 (m, 1H),3.83 (q, J=7.0 Hz, 2H), 3.65-3.54 (m, 1H), 3.30-3.23 (m, 1H), 2.55 (s,3H), 2.33 (dd, J=16.8, 8.4 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H). LCMS forC₁₄H₁₆ClFNO₃ (M+H)⁺: m/z=300.1; Found: 300.0. From peak 2: ¹H NMR (400MHz, DMSO-d₆) δ 7.84 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 4.13-4.00 (m, 1H),3.87-3.77 (m, 2H), 3.65-3.55 (m, 1H), 3.31-3.23 (m, 1H), 2.55 (s, 3H),2.32 (ddd, J=16.9, 8.4, 1.6 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H). LCMS forC₁₄H₁₆ClFNO₃ (M+H)⁺: m/z=300.1; Found: 300.1.

Step 6. Diastereoisomers of4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]pyrrolidin-2-one

The enantiomers from step 5 were each processed individually to thefinal products. A solution of4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (0.402 g,1.34 mmol) (from Step 5) in anhydrous methanol (6.7 mL) under anatmosphere of nitrogen at 0° C. was treated with sodium tetrahydroborate(0.10 g, 2.7 mmol) and stirred at 0° C. for 30 min. The reaction mixturewas quenched with water at 0° C. and poured into water (50 mL)/ethylacetate (100 mL) while stirring. The mixture was warmed to ambienttemperature and the aqueous layer was separated and extracted withadditional ethyl acetate (50 mL). The combined organic extracts werewashed with brine, dried over sodium sulfate, filtered, and concentratedto give white foams. The crude material were purified by flash columnchromatography using acetonitrile (containing 7% methanol) indichloromethane (0%-100%) to give the desired products as mixtures ofdiastereoisomers [from peak 1 (0.40 g, 99%); from peak 2 (0.40 g, 99%)].From peak 1: LCMS for C₁₄H₁₈ClFNO₃ (M+H)⁺: m/z=302.1; Found: 302.0. Frompeak 2: LCMS for C₁₄H₁₈ClFNO₃ (M+H)⁺: m/z=302.1; Found: 302.1.

Step 7. Diastereoisomers of4-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]pyrrolidin-2-one

The mixture of diastereoisomers from step 6 were each processedindividually to the final products. A solution of4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]pyrrolidin-2-one(0.41 g, 1.4 mmol) (from Step 6) in methylene chloride (12 mL) wastreated with N,N-dimethylformamide (0.011 mL, 0.14 mmol) followed bythionyl chloride (0.21 mL, 2.9 mmol) dropwise and stirred at 20° C. for30 min. The reaction mixture was added dropwise to ice cooled saturatedsodium bicarbonate solution and extracted with dichloromethane. Theorganic layer was separated and washed with brine, dried over sodiumsulfate, filtered, and concentrated to give the desired products [frompeak 1 (0.38 g, 87%); from peak 2 (0.39 g, 89%)] along with 17-18% ofthe styrene that formed from chloride elimination. These mixtures wereused without further purification. From peak 1: LCMS for C₁₄H₁₇Cl₂FNO₂(M+H)⁺: m/z=320.1; Found: 320.0. From peak 2: LCMS for C₁₄H₁₇Cl₂FNO₂(M+H)⁺: m/z=320.1; Found: 320.0.

Step 8. Diastereoisomers of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one

The mixture of diastereoisomers from step 7 were each processedindividually to the final products. A mixture of4-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]pyrrolidin-2-one(0.36 g, 1.1 mmol) (from Step 7),3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.19 g, 1.3 mmol), cesiumcarbonate (0.54 g, 1.7 mmol) and potassium iodide (18 mg, 0.11 mmol) inN,N-dimethylformamide (7.4 mL) was heated at 100° C. for 4.5 h. Thereaction mixture was poured into water (30 ml) and extracted with ethylacetate (3×50 mL) to give a mixture of diastereoisomer((S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;(R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;(S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;and(R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one).The mixture of diastereoisomers were purified by preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to givethe desired products [from peak 1 were isolated peak A (compound 345)(0.13 g, 54%) and peak B (compound 346) (0.11 g, 46%); from peak 2 wereisolated peak A (compound 347) (0.15 g, 63%) and peak B (compound 348)(0.14 g, 55%)]. Compound 346: ¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (s, 1H),7.82 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.30 (br s, 1H), 6.23 (q, J=7.0Hz, 1H), 4.05-3.90 (m, 1H), 3.88-3.78 (m, 2H), 3.63-3.53 (m, 1H),3.29-3.20 (m, 1H), 2.54 (s, 3H), 2.38-2.21 (m, 1H), 1.70 (d, J=7.1 Hz,3H), 1.39 (t, J=6.9 Hz, 3H). LCMS for C₂₀H₂₃ClFN₆O₂ (M+H)⁺: m/z=433.2;Found: 433.1. Compound 347: ¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (s, 1H),7.77 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.26 (br s, 2H), 6.24 (q, J=7.0Hz, 1H), 4.04-3.94 (m, 1H), 3.93-3.85 (m, 1H), 3.84-3.77 (m, 1H),3.61-3.53 (m, 1H), 3.27-3.22 (m, 1H), 2.54 (s, 3H), 2.30 (dd, J=18.1,8.6 Hz, 1H), 1.71 (d, J=7.1 Hz, 3H), 1.40 (t, J=6.9 Hz, 3H). LCMS forC₂₀H₂₃ClFN₆O₂ (M+H)⁺: m/z=433.2; Found: 433.1.

Examples 349-352. Diastereoisomers of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile

Step 1. Enantiomers of4-acetyl-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile

A racemic mixture of4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (0.20 g,0.67 mmol) (from Example 345, Step 5) and sodium cyanide (0.057 g, 1.2mmol) in dimethyl sulfoxide (1.5 mL) was stirred at 80° C. for 3 h. Thereaction mixture was poured into water (35 mL) and extracted with ethylacetate (2×50 mL). The combined organic extracts were washed with brine,dried over sodium sulfate, filtered, and concentrated to give a cruderesidue. The crude material was purified by flash column chromatographyusing ether (containing 10% methanol) in hexanes (0%-100%) to give thedesired product (0.15 g, 71%) as a mixture of enantiomers. LCMS forC₁₅H₁₆ClN₂O₃ (M+H)⁺: m/z=307.1; Found: 307.0. The mixture of enantiomerswas separated by chiral HPLC to give the individual enantiomers as peak1 and peak 2 (RT=5.00 min and 10.4 min; Phenomenex Lux Cellulose C-2,21.2×250 mm, 5 micron particle size, eluting with 60% ethanol in hexanesat 18 mL/min).

Step 2. Diastereoisomers of6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(5-oxopyrrolidin-3-yl)benzonitrile

The enantiomers from step 1 were each processed individually to thefinal products. A solution of4-acetyl-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile (frompeak 1: 0.83 g, 2.7 mmol; from peak 2: 0.86 g, 2.8 mmol) in anhydrousmethanol (14 mL) under an atmosphere of nitrogen at 0° C. was treatedwith sodium tetrahydroborate (0.20 g, 5.4 mmol) and stirred at 0° C. for30 min. The reaction mixture was quenched with water at 0° C. and pouredinto water (50 mL)/ethyl acetate (100 mL) while stirring. The mixturewas warmed to ambient temperature and the aqueous layer was separatedand extracted with additional ethyl acetate (50 mL). The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered, and concentrated to give the desired products as mixtures ofdiastereoisomers [from peak 1 (0.83 g, 99%); from peak 2 (0.87 g, 99%)].From peak 1: LCMS for C₁₅H₁₈ClN₂O₃ (M+H)⁺: m/z=309.1; Found: 309.1. Frompeak 2: LCMS for C₁₅H₁₈ClN₂O₃ (M+H)⁺: m/z=309.1; Found: 309.1.

Step 3. Diastereoisomers of6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile

The mixture of diastereoisomers from step 2 were each processedindividually to the final products. A solution of6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(5-oxopyrrolidin-3-yl)benzonitrile(from peak 1: 0.83 g, 2.7 mmol; from peak 2: 0.87 g, 2.8 mmol) inmethylene chloride (23 mL) was treated with N,N-dimethylformamide (0.021mL, 0.27 mmol) followed by thionyl chloride (0.490 mL, 6.72 mmol)dropwise and stirred at 20° C. for 2 h. The reaction mixture was addeddropwise to ice cooled saturated sodium bicarbonate solution andextracted with dichloromethane. The organic layer was separated andwashed with brine, dried over sodium sulfate, filtered, and concentratedto give the desired products as mixtures of diastereoisomers [from peak1 (0.85 g, 97%); from peak 2 (0.90 g, 98%)]. These mixtures were usedwithout further purification. From peak 1: LCMS for C₁₅H₁₇Cl₂N₂O₂(M+H)⁺: m/z=327.1; Found: 327.1. From peak 2: LCMS for C₁₅H₁₇Cl₂N₂O₂(M+H)⁺: m/z=327.1; Found: 327.1.

Step 4. Diastereoisomers of4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile

The mixture of diastereoisomers from step 3 were each processedindividually. A mixture of6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile(from peak 1: 0.85 g, 2.6 mmol; from peak 2: 0.89 g, 2.7 mmol),3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.46 g, 3.1 mmol), cesiumcarbonate (1.3 g, 3.9 mmol) and potassium iodide (43 mg, 0.26 mmol) inN,N-dimethylformamide (17 mL, 220 mmol) was heated at 90° C. for 3 h.

The reaction mixture was poured into water (100 mL)/ethyl acetate (100mL) and filtered through Celite to remove black solids. The aqueouslayer was separated and extracted with ethyl acetate (2×100 mL). Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered, and concentrated to give white foams. The crudematerial were purified by flash column chromatography using methanol indichloromethane (0%-20%) to give the desired products as mixtures ofdiastereoisomers [from peak 1 (0.49 g, 43%); from peak 2 (0.53 g, 44%)].Analytical chiral HPLC analysis of the diastereoisomers from peak 1revealed a mixture of four peaks instead of the desired two due toepimerization. Analysis of the diastereoisomers from peak 2 alsorevealed four peaks. Both sets of mixtures were combined and purifiedvia chiral HPLC to give four individual peaks (RT=6.41 min, 8.13 min,9.93 min, 14.4 min; Phenomenex Lux Cellulose C-2, 21.2×250 mm, 5 micronparticle size, eluting with 60% ethanol in hexanes at 18 mL/min). Thecompounds of peak 1 (compound 351), peak 2 (compound 349), peak 3(compound 352), and peak 4 (compound 350) were then tested in the assaysof Example A3 and B2. Compound 349: ¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (s,1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.30 (br s, 2H), 6.26 (q, J=7.0 Hz,1H), 4.32-4.20 (m, 1H), 4.00-3.91 (m, 1H), 3.90-3.81 (m, 1H), 3.65-3.59(m, 1H), 3.49-3.42 (m, 1H), 2.55 (s, 3H), 1.74 (d, J=7.0 Hz, 3H), 1.43(t, J=6.9 Hz, 3H). LCMS for C₂₁H₂₃ClN₇O₂ (M+H)⁺: m/z=440.2; Found:440.2. Compound 352: ¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.88 (s,1H), 7.56 (s, 1H), 7.30 (br s, 2H), 6.26 (q, J=7.0 Hz, 1H), 4.32-4.19(m, 1H), 3.97-3.82 (m, 2H), 3.67-3.59 (m, 1H), 3.49-3.40 (m, 1H),2.59-2.52 (m, 3H), 1.73 (d, J=7.0 Hz, 3H), 1.42 (t, J=6.9 Hz, 3H). LCMSfor C₂₁H₂₃ClN₇O₂ (M+H)⁺: m/z=440.2; Found: 440.2.

Examples 353 and 354. Diastereomers of4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one

Step 1: 1-(5-Chloro-2-ethoxy-4-fluoro-3-vinylphenyl)ethanone

A mixture of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (13.3g, 38.8 mmol) (from Example 139, Step 1),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.9 mL, 46 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (1.0 g, 1.0 mmol) and potassium carbonate (16g, 120 mmol) in 1,4-dioxane (200 mL) and water (100 mL) was heated at80° C. for 2 hours. The mixture was cooled to rt and extracted withethyl acetate. The extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. Purification on silica gel usingethyl acetate in hexanes (0-30%) gave the desired compound, 7.0 g, 74%.LCMS calculated for C₁₂H₁₃ClFO₂ (M+H)⁺: m/z=243.0; found: 243.1.

Step 2:1-[5-Chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-fluorophenyl]ethanone

AD-mix-alpha (5.8 g, 7.3 mmol) (Aldrich #392758) was stirred intert-butyl alcohol (21 mL) with water (21 mL) for 15 minutes.1-(5-chloro-2-ethoxy-4-fluoro-3-vinylphenyl)ethanone (1.0 g, 4.1 mmol)(from Step 1) was added and the suspension was stirred for 16 hours.Sodium sulfite (6.2 g, 49 mmol) was added and the suspension was stirredfor 15 minutes. The reaction mixture was extracted with ethyl acetate.The extracts were washed with brine and dried over sodium sulfate,filtered and evaporated. Purification on silica gel using ethyl acetatein hexanes (0-80%) gave the desired compound as a racemic mixture, 900mg, 80%. Chiral purification on Phenomenex Lux Cellulose C-2, 21.2×250mm (Chiral Technologies), 5 micron particle size, at flow rate of 18mL/min using 20% ethanol in hexanes gave peak 1 (single enantiomer)(retention time=7.88 minutes) and peak 2 (single enantiomer) (retentiontime=11 minutes); the desired enantiomer was peak 2. LCMS calculated forC₁₂H₁₃ClFO₃ (M-OH)⁺: m/z=259.1; found: 259.1.

Step 3:1-[3-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1-hydroxyethyl)-5-chloro-2-ethoxy-4-fluorophenyl]ethanone

1-[5-Chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-fluorophenyl]ethanone (700mg, 2 mmol) (from Step 2, peak 2) was stirred in 1,2-dichloroethane (6mL) with N,N-diisopropylethylamine (4.0 mL, 23 mmol) and a 1.0 Msolution of tert-butyldimethylsilyl chloride in 1,2-dichloroethane (7.6mL) was added. The mixture was heated to 80° C. for 3 hours and cooledto rt. Evaporation and purification on silica gel using ethyl acetate inhexanes (0-50%) gave the desired compound 800 mg, 80%. LCMS calculatedfor C₁₈H₂₈ClFO₄SiNa (M+Na)⁺: m/z=413.1; found: 413.1.

Step 4:1-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethylmethanesulfonate

1-[3-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1-hydroxyethyl)-5-chloro-2-ethoxy-4-fluorophenyl]ethanone(700 mg, 2.0 mmol) (from Step 3) was stirred in 1,2-dichloroethane (15mL) with triethylamine (2.0 mL, 14 mmol) and methanesulfonic anhydride(670 mg, 3.8 mmol) at rt for 1.5 hours. The mixture was poured intobrine and extracted with dichloromethane. The extracts were dried oversodium sulfate, filtered and evaporated to give the desired compound 830mg, 100%. LCMS calculated for C₁₈H₂₇ClFO₃Si (M-OMs)⁺: m/z=373.1; found:373.1.

Step 5:1-[3-(1-Azido-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-2-ethoxy-4-fluorophenyl]ethanone

1-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethylmethanesulfonate (0.83 g, 1.77 mmol) (from Step 4) was stirred indimethyl sulfoxide (10 mL) and sodium azide (0.12 g, 1.8 mmol) wasadded. The mixture was heated to 50° C. for 1 hour and cooled to rt. Themixture was poured into brine and extracted with ethyl acetate. Theextracts were dried over sodium sulfate, filtered and evaporated to givethe desired compound 736 mg, 100%. LCMS calculated for C₁₈H₂₇ClFN₃O₃SiNa(M+Na)⁺: m/z=438.1; found: 438.1.

Step 6:1-[3-(1-Amino-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-2-ethoxy-4-fluorophenyl]ethanone

1-[3-(1-Azido-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-2-ethoxy-4-fluorophenyl]ethanone(750 mg, 1.8 mmol) (from Step 5) was stirred in tetrahydrofuran (10 mL)with water (0.33 mL) and triphenylphosphine was added. The mixture washeated to 60° C. for 2 hours and cooled to rt. Brine was added and themixture was extracted with ethyl acetate. The extracts were dried oversodium sulfate, filtered and evaporated to give the desired compound 700mg, 100%. LCMS calculated for C₁₈H₃₀ClFNO₃Si (M+H)⁺: m/z=390.2; found:390.2.

Step 7: tert-Butyl(1-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)carbamate

1-[3-(1-Amino-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-2-ethoxy-4-fluorophenyl]ethanone(700 mg, 2.0 mmol) (from Step 6) was stirred in tetrahydrofuran (30 mL)with di-tert-butyldicarbonate (780 mg, 3.6 mmol) andN,N-diisopropylethylamine (0.94 mL, 5.4 mmol) was added. The mixture wasstirred at rt for 30 minutes. Brine was added and the mixture wasextracted with ethyl acetate. The extracts were dried over sodiumsulfate, filtered and evaporated. Purification on silica gel using ethylacetate in hexanes (0-30%) gave the desired compound 550 mg, 60%. LCMScalculated for C₂₃H₃₇ClFNO₅SiNa (M+Na)⁺: m/z=512.2; found: 512.2.

Step 8: tert-Butyl[1-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-hydroxyethyl]carbamate

Tert-Butyl(1-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)carbamate(500 mg, 1.0 mmol) (from Step 7) was stirred in tetrahydrofuran (10 mL)and a 1.0 M solution of tetra-n-butylammonium fluoride intetrahydrofuran (1.5 mL) was added. The mixture was stirred at rt for 30minutes and evaporated. Purification on silica gel using ethyl acetatein hexanes (0-50%) gave the desired compound 238 mg, 60%. LCMScalculated for C₁₇H₂₃ClFNO₅Na (M+Na)⁺: m/z=398.1; found: 398.1.

Step 9:4-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-1,3-oxazolidin-2-one

tert-Butyl[1-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-hydroxyethyl]carbamate(234 mg, 0.62 mmol) (from Step 8) was dissolved in 1,2-dichloroethane(12 mL) and a solution of 2.0 M phosgene in toluene (0.93 mL) was added.The mixture was heated to 80° C. for 1.5 hours. Evaporation andpurification on silica gel using ethyl acetate in hexanes (0-85%) gavethe desired compound, 175 mg, 93%. LCMS calculated for C₁₃H₁₄ClFNO₄(M+H)⁺: m/z=302.1; found: 302.1.

Step 10:4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one

4-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-1,3-oxazolidin-2-one (175mg, 0.58 mmol) was stirred in methanol (10 mL) at 0° C. and sodiumtetrahydroborate (33 mg, 0.87 mmol) was added. The mixture was stirredat rt for 1 hour and evaporated. Water was added and the mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover sodium sulfate, filtered and evaporated to give an approximate 1:1mixture of diastereomers, 175 mg, 99%. LCMS calculated forC₁₃H₁₅ClFNO₄Na (M+Na)⁺: m/z=326.1; found: 326.1.

Step 11:4-[3-chloro-5-(chloroethyl)-6-ethoxy-2-fluorophenyl]-1,3-oxazolidin-2-one

4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one(150 mg, 0.49 mmol) (from Step 10) was stirred in dichloromethane (4 mL)with N,N-dimethylformamide (96 μL) and thionyl chloride (110 μL, 1.5mmol) was added. The mixture was evaporated. Water was added and themixture was extracted with ethyl acetate. The extracts were washed withbrine, dried over sodium sulfate, filtered and evaporated to give thedesired compound, 159 mg, 100%.

Step 12:4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one

4-[3-chloro-5-(chloroethyl)-6-ethoxy-2-fluorophenyl]-1,3-oxazolidin-2-one(160 mg, 0.50 mmol) (from Step 11) was stirred in N,N-dimethylformamide(21 mL) with cesium carbonate (324 mg, 0.99 mmol) and3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (89 mg, 0.60 mmol) wasadded. The mixture was heated to 80° C. for 1.5 hours and cooled to rt.The mixture was diluted with water and extracted with ethyl acetate. Theextracts were washed with brine, dried over sodium sulfate, filtered andevaporated. Purification by preparative LCMS (pH 10) using RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 30 mL/min) separatedthe two diastereomers (peak 1 [compound 353] Rt=4.9 min. and peak 2[compound 354] Rt=5.6 min.); providing compound 354 as the desiredsingle enantiomer, 28 mg, 13%. peak 2: LCMS calculated for C₁₉H₂₁ClFN₆O₃(M+H)⁺: m/z=435.1; found: 435.1. ¹H NMR (300 MHz, CD₃OD): δ 8.15 (s,1H), 7.62 (m, 1H), 6.31 (m, 1H), 5.39 (m, 1H), 4.79 (m, 1H), 4.40 (m,1H), 3.95 (m, 1H), 3.80 (m, 1H), 2.60 (s, 3H), 1.80 (m, 3H), 1.40 (m,3H).

Examples 355-358. Diastereomers of5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one

Step 1: tert-Butyl[2-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-hydroxyethyl]carbamate

0.2 M Osmium tetraoxide in water (10 mL) was added to a solution oftert-butyl [(4-chlorobenzoyl)oxy]carbamate (Lawrence Harris, J Org.Chem, 2011, 76, 358-372). (19 g, 70 mmol) in acetonitrile (210 mL) andstirred for 10 minutes.1-(5-chloro-2-ethoxy-4-fluoro-3-vinylphenyl)ethanone (11.2 g, 46 mmol)(from Example 353, Step 1) as a solution in acetonitrile (210 mL) wasadded to the carbamate solution followed by the addition of water (50mL) and the reaction was stirred for 3 hours at room temperature. Thereaction was quenched with saturated 10 M dipotassium disulfite in water(240 mL) and stirred for 5 minutes. Water was added and the reactionmixture was extracted with ethyl acetate. The extracts were washed withsaturated sodium bicarbonate solution, brine and dried over sodiumsulfate, filtered and evaporated. Purification on silica gel using ethylacetate in hexanes (0-100%) gave the desired compound as a racemicmixture, 16.6 g, 95%. LCMS calculated for C₁₇H₂₃ClFNO₅Na (M+Na)⁺:m/z=398.1; found: 398.0.

Step 2:5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one

The desired single enantiomer (peak 3) was prepared using the sameprocedure as Example 353 (steps 8-12), except that the intermediate fromstep 1 in this example was racemic and thus the final separation of thefour diastereomers occurred in step 12. Chiral purification onPhenomenex Lux Cellulose C-4, 21×250 mm (Chiral Technologies), 5 micronparticle size, at flow rate of 18 mL/min using 30% ethanol in hexanesgave the peak 1: compound 355 (single enantiomer) (retention time=12.7minutes), peak 2: compound 356 (single enantiomer) (retention time=14.2minutes), peak 3: compound 357 (single enantiomer) (retention time=20.3minutes), and peak 4: compound 358 (single enantiomer) (retentiontime=28.9 minutes); the most active enantiomer was peak 3. LCMScalculated for C₁₉H₂₁ClFN₆O₃ (M+H)⁺: m/z=435.1; found: 435.1. ¹H NMR(500 MHz, DMSO-d₆): δ 8.15 (s, 1H), 7.81 (s, 1H), 7.71 (d, 1H), 7.26(bs, 1H), 6.23 (m, 1H), 5.84 (t, 1H), 3.92 (m, 1H), 3.83 (m, 1H), 2.52(s, 3H), 1.75 (d, 3H), 1.40 (m, 3H).

Example 359.5-(3-{1-[4-Amino-5-oxo-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-8(5H)-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

Step 1. 4-Amino-6-iodopyrido[2,3-d]pyrimidin-5(8H)-one

To a suspension of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (from VWR,0.48 g, 3.0 mmol) in DMF (8 mL) was added N-iodosuccinimide (0.80 g, 3.6mmol). The resulting mixture was stirred at ambient temperatureovernight. The reaction mixture was filtered and washed with ethylacetate to give the desired product as yellow solid (0.81 g, 95%). LCMScalculated for C₇H₆IN₄O (M+H)⁺: m/z=289.0; Found: 289.0.

Step 2.5-{3-[1-(4-Amino-6-iodo-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

To a mixture of 4-amino-6-iodopyrido[2,3-d]pyrimidin-5(8H)-one (255 mg,0.885 mmol), cesium carbonate (0.43 g, 1.3 mmol) and potassium iodide(14.7 mg, 0.0885 mmol) in DMF (9.4 mL) was added5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide(325 mg, 0.885 mmol) (from example 25 step 1) and the mixture wasstirred at 140° C. for 1 h. The mixture was diluted with methanol andpurified on RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) to give the desired compound (221 mg, 40%). LCMS calculatedfor C₂₅H₂₅ClIN₆O₃ (M+H)⁺: m/z=619.1; Found: 619.0.

Step 3.5-(3-{1-[4-Amino-5-oxo-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-8(5H)-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

A mixture of5-{3-[1-(4-amino-6-iodo-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(10.3 mg, 0.0166 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.5 mg,0.018 mmol), sodium carbonate (3.5 mg, 0.033 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (1:1) (1.6 mg, 0.0020 mmol) in acetonitrile (0.1mL)/water (0.03 mL) was degassed with N₂ and the stirred at 90° C. for2.0 h. The mixture was diluted with methanol and purified on RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to givethe desired product (2.7 mg, 30%). LCMS calculated for C₂₈H₂₈ClN₅O₃(M+H)⁺: m/z=559.2; Found: 559.2.

Example 360.5-{3-[1-(4-Amino-6-methyl-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

To a microwave vial was charged with5-{3-[1-(4-amino-6-iodo-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(24.0 mg, 0.0388 mmol), potassium trifluoro(methyl)borate (9.4 mg, 0.078mmol), palladium acetate (2.1 mg, 0.0094 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (8.7 mg, 0.019mmol) and cesium carbonate (38 mg, 0.12 mmol) in toluene (0.5 mL) andwater (0.06 mL). The reaction vial was evacuated under high vacuum andbackfilled with N₂. The reaction mixture was heated at 100° C.overnight. The mixture was diluted with methanol, filtered and purifiedon RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% trifluoroacetic acid, at flow rateof 30 mL/min) to give the desired product as bis-TFA salt (3.0 mg, 15%).LCMS calculated for C₂₆H₂₈ClN₆O₃ (M+H)⁺: m/z=507.2; Found: 507.0.

Examples 361-363. Diastereomers of4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile

Based on the stereochemistry of Example 269, the stereochemistry of eachdiastereomer is believed to be4-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile(Example 361),4-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile(Example 362), and4-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile(Example 363) (structures shown below)

Synthesis of Example 361:

To(R)-4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-(azetidin-3-yl)-6-chloro-3-methoxybenzonitrile(6.00 g, 14.3 mmol) was added methanol (72 mL). To the resultingsuspension was added (S)-(−)-methyloxirane (2.01 mL, 28.6 mmol) at roomtemperature and the mixture was stirred at room temperature for 19 h.Additional (S)-(−)-methyloxirane (0.50 mL, 7.2 mmol) was added and thestirring was continued for an additional hour. To the reaction mixturewas added water (280 mL) and the cloudy solution was stirred. Themixture was extracted with methylene chloride (300 mL×4). The organiclayer was combined and washed with brine (50 mL) and concentrated. Thecrude product was purified by silica column chromatography eluted withMeOH (contained about 0.5% ammonium hydroxide) in methylene chloride.The fractions contained product were collected and evaporated todryness. This residue was further purified by preparative HPLC to givethe title compound. A sample of the title compound was analyzed by NMRspectroscopy and mass spectrometry and gave the following data. ¹H NMR(500 MHz, DMSO) δ 8.11 (s, 1H), 7.47 (s, 1H), 7.30 (br s, 2H), 6.24 (q,J=7.0 Hz, 1H), 4.32 (br s, 1H), 4.07 (m, 1H), 3.94 (m, 2H), 3.65 (s,3H), 3.59 (m, 1H), 3.08 (m, 2H), 2.56 (s, 3H), 2.38-2.19 (m, 2H), 1.73(d, J=7.1 Hz, 3H), 1.00 (d, J=6.2 Hz, 3H) ppm. LCMS for C₂₂H₂₇ClN₇O₂(M+H)⁺: m/z=456.2; found: 456.2.

Synthesis of Example 362:

To(S)-4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-(azetidin-3-yl)-6-chloro-3-methoxybenzonitrile(293.0 mg, 0.73 mmol) was added methanol (3.7 mL). To the resultingsuspension was added (R)-(+)-methyloxirane 103 μL, 1.46 mmol) at roomtemperature and the mixture was stirred at room temperature for 19 h.Additional (R)-(+)-methyloxirane (51.3 μL, 0.73 mmol) was added and thestirring was continued for additional 2.5 hours. To the reaction mixturewas added water (14 mL) and the cloudy solution was stirred. The mixturewas extracted with methylene chloride (4×16 mL). The organic layer wascombined and washed with brine (50 mL) and concentrated. The crudeproduct was purified by silica column chromatography, eluted with MeOH(contained about 0.5% ammonium hydroxide) in methylene chloride. Thefractions contained product were collected and evaporated to dryness.This residue was further purified by preparative HPLC to give the titlecompound. A sample of the title compound was analyzed by NMRspectroscopy and mass spectrometry and gave the following data. ¹H NMR(500 MHz, DMSO) δ 8.11 (s, 1H), 7.47 (s, 1H), 7.30 (br s, 2H), 6.24 (q,J=7.0 Hz, 1H), 4.37 (br s, 1H), 4.09 (m, 2H), 3.93 (m, 2H), 3.65 (s,3H), 3.59 (m, 1H), 3.12 (m, 2H), 2.56 (s, 3H), 2.39-2.26 (m, 2H), 1.73(d, J=7.1 Hz, 3H), 1.00 (d, J=6.2 Hz, 3H) ppm. LCMS for C₂₂H₂₇ClN₇O₂(M+H)⁺: m/z=456.2; found: 456.2.

Synthesis of Example 363:

To(R)-4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-(azetidin-3-yl)-6-chloro-3-methoxybenzonitrile(6.0 g, 14.3 mmol) was added methanol (72 mL). To the resultingsuspension was added (R)-(+)-methyloxirane (2.01 mL, 28.6 mmol) at roomtemperature and the mixture was stirred at room temperature for 18 h. Tothe reaction mixture was added water (280 mL) and the cloudy solutionwas stirred. The mixture was extracted with methylene chloride (300mL×4). The organic layer was combined and washed with brine (50 mL) andconcentrated. The crude product was purified by silica columnchromatography, eluted with MeOH (contained about 0.5% ammoniumhydroxide) in methylene chloride. The fractions contained product werecollected and evaporated to dryness. This residue was further purifiedby preparative HPLC to give the title compound. A sample of the titlecompound was analyzed by NMR spectroscopy and mass spectrometry and gavethe following data. ¹H NMR (500 MHz, DMSO) δ 8.11 (s, 1H), 7.46 (s, 1H),7.29 (br s, 2H), 6.24 (q, J=7.0 Hz, 1H), 4.31 (d, J=4.2 Hz, 1H),4.11-4.00 (m, 1H), 3.98-3.90 (m, 1H), 3.65 (s, 3H), 3.61-3.53 (m, 2H),3.07 (m, 2H), 2.56 (s, 3H), 2.28 (d, J=5.9 Hz, 2H), 1.73 (d, J=7.1 Hz,3H), 1.00 (d, J=6.2 Hz, 3H) ppm.

Three HPLC methods were developed to separate the stereoisomers from thecompound of Example 269. Method A was developed to separate thediastereomer Example 361 from Example 269. The retention times ofExample 361 from Example 269 are 15.7 min and 11.5 min respectively.Chromatographic conditions are described in Table B1.

TABLE B1 Column Phenomenex Cellulose 3 (250 mm, 4.6 mm, 5 micron) Mobile89.9% hexane/10% ethanol/0.1% diethylamine (pre-mixed) Phase Flow Rate 1mL/min Run Time 30 min Detection 247 nm Wavelength Quantitation Peakarea ratio

Method B was developed to separate the diastereomer Example 362 fromExample 269. The retention times of Example 362 from Example 269 are26.4 min and 21.7 min respectively. Chromatographic conditions aredescribed in Table B2.

TABLE B2 Column Phenomenex Cellulose 4 (250 mm, 4.6 mm, 5 micron) Mobile84.9% hexane/15% ethanol/0.1% diethylamine (pre-mixed) Phase Flow Rate 1mL/min Run Time 40 min Detection 247 nm Wavelength Quantitation Peakarea ratio

Method C was developed to separate the three stereoisomers Example 361,Example 362 and Example 363 from Example 269. The stereoisomers Example361, Example 362 and Example 363 elute at retention time 12.9 min as abroad band while Example 269 elutes at retention time 14.3 min. Anestimation of the level of the enantiomer, Example 363 can be made by acombination of data from Methods A, B, and C. Chromatographic conditionsare described in Table B3.

TABLE B3 Column Phenomenex Cellulose 1 (250 mm, 4.6 mm, 5 micron) MobilePhase 88% hexanes, 12% ethanol (conatins 0.1% diethylamine) Flow Rate 1mL/min Run Time 25 min Detection 247 nm Wavelength Quantitation Peakarea ratio

Example A1: PI3K Enzyme Assay

PI3-Kinase luminescent assay kit including lipid kinase substrate,D-myo-phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D(+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2),biotinylated I(1,3,4,5)P4, PI(3,4,5)P3 Detector Protein is purchasedfrom Echelon Biosciences (Salt Lake City, Utah). AlphaScreen™ GSTDetection Kit including donor and acceptor beads was purchased fromPerkinElmer Life Sciences (Waltham, Mass.). PI3Kδ (p110δ/p85α) ispurchased from Millipore (Bedford, Mass.). ATP, MgCl₂, DTT, EDTA, HEPESand CHAPS are purchased from Sigma-Aldrich (St. Louis, Mo.).

AlphaScreen™ Assay for PI3Kδ

The kinase reaction are conducted in 384-well REMP plate from ThermoFisher Scientific in a final volume of 40 μL. Inhibitors are firstdiluted serially in DMSO and added to the plate wells before theaddition of other reaction components. The final concentration of DMSOin the assay is 2%. The PI3K assays are carried out at room temperaturein 50 mM HEPES, pH 7.4, 5 mM MgCl₂, 50 mM NaCl, 5 mM DTT and CHAPS0.04%. Reactions are initiated by the addition of ATP, the finalreaction mixture consisted of 20 μM PIP2, 20 μM ATP, 1.2 nM PI3Kδ areincubated for 20 minutes. 10 μL of reaction mixture are then transferredto 5 μL 50 nM biotinylated I(1,3,4,5)P4 in quench buffer: 50 mM HEPES pH7.4, 150 mM NaCl, 10 mM EDTA, 5 mM DTT, 0.1% Tween-20, followed with theaddition of 10 μL AlphaScreen™ donor and acceptor beads suspended inquench buffer containing 25 nM PI(3,4,5)P3 detector protein. The finalconcentration of both donor and acceptor beads is 20 mg/ml. After platesealing, the plate are incubated in a dark location at room temperaturefor 2 hours. The activity of the product is determined on Fusion-alphamicroplate reader (Perkin-Elmer). IC₅₀ determination is performed byfitting the curve of percent control activity versus the log of theinhibitor concentration using the GraphPad Prism 3.0 software.

Example A2: PI3K Enzyme Assay

Materials: Lipid kinase substrate, phophoinositol-4,5-bisphosphate(PIP2), are purchased from Echelon Biosciences (Salt Lake City, Utah).PI3K isoforms α, β, δ and γ are purchased from Millipore (Bedford,Mass.). ATP, MgCl₂, DTT, EDTA, MOPS and CHAPS are purchased fromSigma-Aldrich (St. Louis, Mo.).

The kinase reaction are conducted in clear-bottom 96-well plate fromThermo Fisher Scientific in a final volume of 24 μL. Inhibitors arefirst diluted serially in DMSO and added to the plate wells before theaddition of other reaction components. The final concentration of DMSOin the assay is 0.5%. The PI3K assays are carried out at roomtemperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT and CHAPS0.03%. The reaction mixture is prepared containing 50 μM PIP2, kinaseand varying concentration of inhibitors. Reactions are initiated by theaddition of ATP containing 2.2 μCi [γ-³³P]ATP to a final concentrationof 1000 μM. The final concentration of PI3K isoforms α, β, δ and γ inthe assay were 1.3, 9.4, 2.9 and 10.8 nM, respectively. Reactions areincubated for 180 minutes and terminated by the addition of 100 μL of 1M potassium phosphate pH 8.0, 30 mM EDTA quench buffer. A 100 μL aliquotof the reaction solution are then transferred to 96-well MilliporeMultiScreen IP 0.45 μm PVDF filter plate (The filter plate is prewettedwith 200 μL 100% ethanol, distilled water, and 1 M potassium phosphatepH 8.0, respectively). The filter plate is aspirated on a MilliporeManifold under vacuum and washed with 18×200 μL wash buffer containing 1M potassium phosphate pH 8.0 and 1 mM ATP. After drying by aspirationand blotting, the plate is air dried in an incubator at 37° C.overnight. Packard TopCount adapter (Millipore) is then attached to theplate followed with addition of 120 μL Microscint 20 scintillationcocktail (Perkin Elmer) in each well. After the plate sealing, theradioactivity of the product is determined by scintillation counting onTopcount (Perkin-Elmer). IC₅₀ determination is performed by fitting thecurve of percent control activity versus the log of the inhibitorconcentration using the GraphPad Prism 3.0 software.

Example A3: PI3Kδ Scintillation Proximity Assay

Materials

[γ-³³P]ATP (10 mCi/mL) was purchased from Perkin-Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3Kδ (p110δ/p85α) was purchased from Millipore(Bedford, Mass.). ATP, MgCl₂, DTT, EDTA, MOPS and CHAPS were purchasedfrom Sigma-Aldrich (St. Louis, Mo.). Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from GE healthcare life sciences(Piscataway, N.J.).

The kinase reaction was conducted in polystyrene 384-well matrix whiteplate from Thermo Fisher Scientific in a final volume of 25 μL.Inhibitors were first diluted serially in DMSO and added to the platewells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 0.5%. The PI3K assays werecarried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mMDTT and CHAPS 0.03%. Reactions were initiated by the addition of ATP,the final reaction mixture consisted of 20 μM PIP2, 20 μM ATP, 0.2 μCi[γ-³³P] ATP, 4 nM PI3Kδ. Reactions were incubated for 210 min andterminated by the addition of 40 μL SPA beads suspended in quenchbuffer: 150 mM potassium phosphate pH 8.0, 20% glycerol. 25 mM EDTA, 400μM ATP. The final concentration of SPA beads was 1.0 mg/mL. After theplate sealing, plates were shaken overnight at room temperature andcentrifuged at 1800 rpm for 10 minutes, the radioactivity of the productwas determined by scintillation counting on Topcount (Perkin-Elmer).IC₅₀ determination was performed by fitting the curve of percent controlactivity versus the log of the inhibitor concentration using theGraphPad Prism 3.0 software. IC₅₀ data for the Examples is presented inTable 10 as determined by Assay A3. IC₅₀ data for Examples 361 and 363is shown in Table 10a as determined by Assay A2.

TABLE 10 Example # PI3Kδ SPA IC₅₀ (nM)*  1 +  2 +  3 +  4 +  5 +  6 + 7 +  8 +  9 +  10 +  11 +  12 ++++  13 +  14 +  15 +  16 +  17 +  18 + 19 +  20 (1^(st) peak) +  20 (2^(nd) peak) +++  21 +  22 +  23 +  24 + 25 (1^(st) peak) ++++  25 (2^(nd) peak) +  26 +  27 +  28 +  29 +  30 + 31 +  32 +  33 +  34 +  35 +  36 +  37 +  38 ++  39 +++  40 ++  41 +++ 42 +  43 +  44 +  45 +  46 +  47 +  48 +  49 +  50 +  51 +  52 +  53 + 54 ++  55 ++  56 ++  57 +  58 +  59 +  60 +  61 +  62 +  63 +  64 + 65 +  66 +  67 (1^(st) peak) +  68 (1^(st) peak) +  69 +  70 +  71 + 72 +  73 +  74 (1^(st) peak) +  75 +  76 +  77 +  78 +  79 +  80 +  81+++  82 +  83 +  84 +++  85 +++  86 +  87 +  88 +  89 +  90 +  91 + 92 +  93 +  94 +  95 +  96 +  97 +  98 +  99 + 100 + 101 + 102 + 103 +104 + 105 + 106 + 107 + 108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 +116 + 117 + 118 + 119 + 120 + 121 + 122 + 123 + 124 + 125 + 126 + 127 +128 + 129 + 130 + 131 + 132 + 133 + 134 + 135 + 136 + 137 + 138 + 139(1^(st) peak) + 140 + 141 + 142 + 143 + 144 + 145 + 146 + 147 + 148 +149 + 150 + 151 + 152 + 153 + 154 + 155 + 156 + 157 + 158 + 159 + 160 +161 + 162 + 163 + 164 + 165 + 166 + 167 + 168 + 169 + 170 + 171 + 172 +173 + 174 + 175 + 176 + 177 + 178 + 179 + 180 + 181 + 182 + 183 + 184 +185 + 186 + 187 + 188 + 189 + 190 + 191 + 192 ++ 193 +++ 194 + 195 +196 + 197 + 198 + 199 + 200 + 201 + 202 + 203 + 204 + 205 + 206 + 207 +208 + 209 ++ 210 + 211 + 212 + 213 + 214 + 215 + 216 + 217 + 218 + 219 +220 + 221 + 222 + 223 + 224 + 225 + 226 + 227 + 228 + 229 + 230 + 231 +232 + 233 + 234 + 235 + 236 + 237 + 238 + 239 + 240 + 241 + 242 + 243 +244 + 245 + 246 + 247 + 248 + 249 + 250 + 251 + 252 + 253 + 254 + 255 +256 + 257 + 258 + 259 + 260 + 261 + 262 + 263 + 264 + 265 + 266 + 267 +268 + 269 + 270 + 271 + 272 + 273 + 274 + 275 + 276 + 277 + 278 + 279 +280 + 281 + 282 + 283 + 284 + 285 + 286 + 287 + 288 + 289 + 290 + 291 +292 + 293 + 294 + 295 + 296 + 297 + 298 (1^(st) peak) + 299 + 300 +301 + 302 + 303 + 304 + 305 + 306 + 307 + 308 + 309 + 313 (2^(nd)peak) + 314 (2^(nd) peak) + 315 + 316 + 317 + 318 + 319 + 320 + 321(1^(st) peak) + 322 (1^(st) peak) + 326 + 327 + 328 + 329 + 330 + 331 +332 + 333 + 334 + 335 + 336 + 337 + 338 + 339 + 340 + 341 + 342 + 343 +344 + 310 + 311 + 323 (1^(st) peak) + 323 (2^(nd) peak) + 323 (3^(rd)peak) +++ 323 (4^(th) peak) + 324 (1^(st) peak) +++ 324 (2^(nd) peak) +325 + 345 +++ 346 + 347 + 348 +++ 349 + 350 +++++ 351 +++ 352 + 353+++++ 354 + 355 +++ 356 +++ 357 + 358 +++++ 359 + 360 + 362 + *columnsymbols: + refers to ≤10 nM ++ refers to >10 nM to 50 nM +++ refersto >50 nM to 200 nM ++++ refers to >200 nM to 500 nM +++++ refersto >500 nM

TABLE 10a Example # PI3Kδ IC₅₀ (nM)* 361 +++++ 363 +++ *columnsymbols: + refers to ≤10 nM ++ refers to >10 nM to 50 nM +++ refersto >50 nM to 200 nM ++++ refers to >200 nM to 500 nM +++++ refersto >500 nM

Example B1: B Cell Proliferation Assay

To acquire B cells, human PBMC are isolated from the peripheral blood ofnormal, drug free donors by standard density gradient centrifugation onFicoll-Hypague (GE Healthcare, Piscataway, N.J.) and incubated withanti-CD19 microbeads (Miltenyi Biotech, Auburn, Calif.). The B cells arethen purified by positive immunosorting using an autoMacs (MiltenyiBiotech) according to the manufacture's instruction.

The purified B cells (2×10⁵/well/200 μL) are cultured in 96-wellultra-low binding plates (Corning, Corning, N.Y.) in RPMI1640, 10% FBSand goat F(ab′)2 anti-human IgM (10 μg/ml) (Invitrogen, Carlsbad,Calif.) in the presence of different amount of test compounds for threedays. [³H]-thymidine (1 μCi/well) (PerkinElmer, Boston, Mass.) in PBS isthen added to the B cell cultures for an additional 12 hours before theincorporated radioactivity is separated by filtration with water throughGF/B filters (Packard Bioscience, Meriden, Conn.) and measured by liquidscintillation counting with a TopCount (Packard Bioscience).

Example B2: Pfeiffer Cell Proliferation Assay

Pfeiffer cell line (diffuse large B cell lymphoma) are purchased fromATCC (Manassas, Va.) and maintained in the culture medium recommended(RPMI and 10% FBS). To measure the anti-proliferation activity of thecompounds, the Pfeiffer cells are plated with the culture medium (2×10³cells/well/per 200 μl) into 96-well ultra-low binding plates (Corning,Corning, N.Y.), in the presence or absence of a concentration range oftest compounds. After 3-4 days, [³H]-thymidine (1 μCi/well)(PerkinElmer, Boston, Mass.) in PBS is then added to the cell culturefor an additional 12 hours before the incorporated radioactivity isseparated by filtration with water through GF/B filters (PackardBioscience, Meridenj, Conn.) and measured by liquid scintillationcounting with a TopCount (Packard Bioscience). IC50 data for selectcompounds is presented in Table 11.

TABLE 11 Example # Pfeiffer IC₅₀ (nM)*  67 (1^(st) peak) +  68 (1^(st)peak) +  75 +  96 + 102 + 103 ++ 104 ++ 111 + 114 + 121 ++ 139 (1^(st)peak) + 140 + 142 + 144 + 148 + 149 + 152 + 154 + 157 ++ 163 ++ 167 +177 + 191 + 195 + 196 + 198 + 200 + 213 + 214 + 215 + 219 + 220 + 221 +222 + 248 + 257 + 262 + 264 + 268 + 269 + 270 + 271 + 300 + 303 + 313(2^(nd) peak) + 314 (2^(nd) peak) + 315 + 354 + 357 + 346 + 347 + 349 +*column symbols: + refers to ≤10 nM ++ refers to >10 nM to 50 nM

Example C: Akt Phosphorylation Assay

Ramos cells (B lymphocyte from Burkitts lymphoma) are obtained from ATCC(Manassas, Va.) and maintained in RPMI1640 and 10% FBS. The cells (3×10⁷cells/tube/3 mL in RPMI) are incubated with different amounts of testcompounds for 2 hrs at 37° C. and then stimulated with goat F(ab′)2anti-human IgM (5 μg/mL) (Invitrogen) for 17 minutes in a 37° C. waterbath. The stimulated cells are spun down at 4° C. with centrifugationand whole cell extracts are prepared using 300 μL lysis buffer (CellSignaling Technology, Danvers, Mass.). The resulting lysates aresonicated and supernatants are collected. The phosphorylation level ofAkt in the supernatants are analyzed by using PathScan phospho-Akt1(Ser473) sandwich ELISA kits (Cell Signaling Technology) according tothe manufacturer's instruction.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound, which is5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one,or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, which is(R)-5-{3-[(R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one,or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, which is(R)-5-{3-[(S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one,or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, which is(S)-5-{3-[(S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one,or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, which is(S)-5-{3-[(R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one,or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.
 7. A pharmaceutical composition comprising a compound of claim2, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 8. A pharmaceutical compositioncomprising a compound of claim 3, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.
 9. Apharmaceutical composition comprising a compound of claim 4, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 10. A pharmaceutical compositioncomprising a compound of claim 5, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.
 11. Acompound, which is5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one.12. The compound of claim 11, which is(R)-5-{3-[(R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one.13. The compound of claim 11, which is(R)-5-{3-[(S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one.14. The compound of claim 11, which is(S)-5-{3-[(S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one.15. The compound of claim 11, which is(S)-5-{3-[(R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one.16. A pharmaceutical composition comprising a compound of claim 11 andat least one pharmaceutically acceptable carrier.
 17. A pharmaceuticalcomposition comprising a compound of claim 12 at least onepharmaceutically acceptable carrier.
 18. A pharmaceutical compositioncomprising a compound of claim 13 and at least one pharmaceuticallyacceptable carrier.
 19. A pharmaceutical composition comprising acompound of claim 14 and at least one pharmaceutically acceptablecarrier.
 20. A pharmaceutical composition comprising a compound of claim15 and at least one pharmaceutically acceptable carrier.